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1 The Role of Oral Antidiabetic Therapy Jane Weinreb, MD Chief, Diabetes Program VA Greater Los Angeles Healthcare System Clinical Professor of Medicine.

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Presentation on theme: "1 The Role of Oral Antidiabetic Therapy Jane Weinreb, MD Chief, Diabetes Program VA Greater Los Angeles Healthcare System Clinical Professor of Medicine."— Presentation transcript:

1 1 The Role of Oral Antidiabetic Therapy Jane Weinreb, MD Chief, Diabetes Program VA Greater Los Angeles Healthcare System Clinical Professor of Medicine David Geffen School of Medicine at UCLA

2 2 Objectives To review major pathophysiologic defects in Type 2 Diabetes and targeted sites for medications To review available classes as well as specific oral antidiabetic medications: mechanism of action, efficacy, adverse effects Discuss role of combination therapy Discuss AACE Diabetes Roadmap and case presentation

3 3 Overview of Glucose Regulation -cell insulin secretion  -cell insulin secretion Glucose Amended from Dinneen SF. Diabetes Med. 1997;14(suppl 3):S Defective insulin secretion Insulin action Resistance to insulin action Persistent Hepatic Glucose Output Sulfonylureas Meglitinides DPP-IV Inhibitors Metformin Thiazolidinediones Alpha glucosidase inhibitors

4 4 Overview of Available Agents Biguanides –Metformin Secretagogues –Sulfonylureas: Glipizide, Glyburide, Glimepiride –Glinides: Nateglinide, Repaglinide Thiazolidinediones –Pioglitazone, Rosiglitazone Alpha Glucosidase Inhibitors –Acarbose, Miglitol Dipeptidyl-Peptidase 4 Inhibitors –Sitagliptin Bile Acid Sequestrant –Colesevalam AACE Diabetes Melllitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007

5 5 Biguanide Agent in Class: Metformin Mechanism of action: poorly understood, but its primary effect is to reduce hepatic glucose production in the presence of insulin Efficacy: lowers A1C by 1 to 2%, maximum effective dose is 2 grams/d Major advantages: – Lack of weight gain or modest weight loss – Absence of or infrequent hypoglycemia AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Diabetes Care, Vol 31(12):

6 6 Biguanide Adverse effects mainly GI: abdominal pain, bloating, nausea, and diarrhea (minimize by slow titration) Contraindication: renal dysfunction, Cr >1.5 mg/dL in men and Cr > 1.4 mg/dL in women Avoid in patients with hepatic dysfunction, CHF, metabolic acidosis, dehydration, and alcoholism Available combinations with sulfonylureas, thiazolidinediones, repaglinide, and sitagliptin AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Diabetes Care, 31(12):10-11, 2008

7 7 Secretagogues: Sulfonylureas Agents in Class: Glipizide, Glyburide, and Glimepiride Mechanism of action: increase insulin secretion from pancreatic beta cells Efficacy: lower A1C by 1-2%; glucose-lowering effect usually plateaus at one half of the maximum recommended dose Nonglycemic effects: weight gain is common Major Advantages: –Long track record of safety –Low price of generic preps AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Diabetes Care, 31(12):10-11, 2008

8 8 Secretagogues: Sulfonylureas Adverse effect: mainly hypoglycemia, which can be prolonged and more frequent in elderly or with impaired renal function (glipizide and glimepiride may be preferred in elderly patient) Avoid in hepatic and renal impairment Available combinations with metformin, both thiazolidinediones, and acarbose AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Diabetes Care, 31(12):10-11, 2008

9 9 Secretagogues: Glinides Agents in Class: Nateglinide, Repaglinide Mechanism of action: stimulate a rapid but short-lived release of insulin that lasts for 1-2 hours, therefore should be used to target postprandial glucose levels Efficacy: similar to SU’s for repaglinide; nateglinide is less efficacious in A1C lowering ( %) Nonglycemic effect: weight gain similar to SU AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Diabetes Care, 31(12):10-11, 2008

10 10 Secretagogues: Glinides Adverse effect: –Much less hypoglycemia than SU –Many drug-drug interactions. Most concerning is gemfibrozil which increases repaglinide concentration and may result in prolonged lows. Used with caution in patients with hepatic impairment Nateglinide is renally cleared, whereas this is minimal for repaglinide  latter can be used with renal impairment Available combination: repaglinide with metformin AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Diabetes Care, 31(12):10-11, 2008

11 11 Thiazolidinediones Agents in class: Pioglitazone, Rosiglitazone Mechanism of action: Enhancing peripheral insulin sensitivity, especially at the muscle and adipose tissue, via activation of PPAR  (peroxisome proliferator-activated receptor gamma). Efficacy: lower A1C 0.8 to 1.5% (decrease in glucose may not be apparent for 4 weeks and maximum efficacy of dose may not be observed for 4-6 months) Nonglycemic effects: –weight gain- modestly reduce blood pressure –enhances fibrinolysis - improve endothelial dysfunction AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Diabetes Care, 31(12):10-11, 2008

12 12 Thiazolidinediones Major advantages: – absence of hypoglycemia when used as monotherapy – no reliance on renal excretion. Adverse effects: weight gain, edema, anemia, and peripheral fractures in women Contraindications: should not be used in patients with CHF (New York Heart Association class III or IV cardiac disease and functional capacity) or hepatic impairment with ALT > 2.5 times the upper normal limits Available combinations with metformin and sulfonylurea AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Diabetes Care, 31(12):10-11, 2008

13 13 Alpha-Glucosidase Inhibitors Agents in Class: Acarbose, Miglitol Mechanisms of action: decrease the rate of digestion for polysaccharides in the proximal small intestine, primarily lowering postprandial glucose levels Efficacy: lower A1C by 0.5 to 1.0% Adverse effects: flatulence, diarrhea, and abdominal discomfort (minimize by slow titration). Available combination with sulfonylurea AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Diabetes Care, 31(12):10-11, 2008

14 14 Dipeptidyl-Peptidase 4 Inhibitors Agent in Class: Sitagliptin, Saxagliptin Mechanism of action: –slows the inactivation of incretin hormones (glucagon- like peptide 1 and glucose-dependent insulinotropic polypeptide)  Increases glucose-stimulated insulin secretion  Causes glucose-stimulated glucagon suppression –primarily lowers postprandial glucose levels but has also been shown to reduce fasting plasma glucose AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Diabetes Care, Vol 31(12):1-11, 2008

15 15 Inhibition of DPP-IV Increases Active Portal GLP-1 and GIP DPP-IV inhibitors exhibit both short term and long term actions of GLP-1 –Augment glucose induced insulin secretion –Inhibit glucagon secretion –Slow gastric emptying –Increase insulin biosynthesis –Promote beta cell differentiation T ½=1-2mins

16 16 Dipeptidyl-Peptidase 4 Inhibitors Efficacy: Lower HbA1C by 0.8% Nonglycemic effect: weight neutral Adverse effects: well tolerated, no hypoglycemia when used as monotherapy. More recently reported to be associated with pancreatitis, ?causative? Available combination with metformin AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Diabetes Care, Vol 31(12):1-11, 2008

17 Bile Acid Sequestrant  Agent in Class: Colesevalam  Mechanism of action uncertain  Efficacy:Lowers the A1C 0.5-8% when added to metformin, sulfonylurea or insulin  Not studied as monotherapy or in combination with incretins or TZD’s  Significant LDL-C reductions of % vs. placebo Bays HE, et al. Arch Intern Med. In press. Fonseca VA, et al. Diabetes Care. 2008; 31: Goldberg RB, et al. Arch Intern Med. 2008; 168:

18 Colesevelam  Take with meals and liquid either 6 tablets once daily or 3 tablets twice daily  No special considerations or dosage adjustments with hepatic impairment or renal disease  Contraindications:  History of bowel obstruction  Serum triglycerides >500 mg/dL  History of hypertriglyceridemia-induced pancreatitis Welchol ® (colesevelam HCl) prescribing information. Daiichi Sankyo, Inc., Parsippany, NJ. January 2008.

19 Colesevelam: Drug Interactions Drugs with a known interaction with colesevelam- administer 4 hours prior to colesevalam Glyburide, levothyroxine, and oral contraceptives containing ethinyl estradiol and norethindrone Drugs with postmarketing reports consistent with potential drug-drug interactions when coadministered with colesevelam Phenytoin- Should be administered 4 hrs before colesevalam Warfarin- No noted problem with colesevalam coadministration, but study did not eval INR Drugs that do not interact with colesevelam based on in vitro or in vivo testing Cephalexin, ciprofloxacin, digoxin, warfarin, fenofibrate, lovastatin, metformin, metoprolol, pioglitazone, quinidine, repaglinide, valproic acid, verapamil

20 Colesevelam in Type 2 DM: Adverse Reactions * Event DescriptionNumber of Patients (%) Colesevalam N = 566 Placebo N = 562 Constipation49 (8.7)11 (2.0) Nasopharyngitis23 (4.1)20 (3.6) Dyspepsia22 (3.9)8 (1.4) Hypoglycemia17 (3.0)13 (2.3) Nausea17 (3.0)8 (1.4) Hypertension16 (2.8)9 (1.6) *Placebo-Controlled Clinical Studies of Colesevelam Add-on Combination Therapy with Metformin, Insulin, Sulfonylureas: Adverse Reactions Reported in ≥2% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality. Colesevelam HCl prescribing information, January 2008.

21 21 Considerations in the Management of Type 2 Diabetes Monotherapy vs. Combination Therapy

22 22 United Kingdom Prospective Diabetes Study (UKPDS) *Conventional therapy defined as dietary advice given at 3-month intervals where FPG was targeted at best levels feasible in clinical practice. If FPG exceeded 270 mg/dL, then patients were re-randomized to receive non-intensive metformin, chlorpropamide, glibenclamide, or insulin. If FPG exceeded 270 mg/dL again, then those on SU would have metformin added. If FPG exceeded 270 mg/dL after this, then insulin was substituted. Adapted with permission from UK Prospective Diabetes Study (UKPDS 34) Group. Lancet. 1998;352: Traditional Monotherapies Do Not Maintain A1C Control Over Time Conventional* Insulin Glibenclamide (glyburide) Metformin Median A1C (%) Time From Randomization (Years) ADA Goal

23 23 Two Year Efficacy of Pioglitazone: Time Course of A1C Pioglitazone

24 24 ADOPT: A Diabetes Outcome Progression Trial Rosiglitazone Sustained A1C Over Time* Time (years) HbA1C (%) RSG GLYB MET Treatment Difference at 4 Years RSG vs MET –0.13 (–0.22 to –0.05), P=.002 RSG vs GLYB –0.42 (–0.50 to –0.33), P<.001 *Mean A1C values per visit are based on a repeated measures mixed model. Kahn SE et al. N Engl J Med. 2006;355: Number of patients:

25 25 Why Combination Therapy Make Sense Treat to Fail vs. Treat to succeed

26 26 Glucose absorption Hepatic glucose overproduction Beta-cell dysfunction Insulin resistance Major Targeted Sites of Oral Drug Classes DPP-4=dipeptidyl peptidase-4; TZDs=thiazolidinediones. DeFronzo RA. Ann Intern Med. 1999;131:281–303. Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483. Pancreas ↓Glucose level Muscle and fat Liver Biguanides TZDsBiguanides Sulfonylureas Glinides TZDs Alpha- glucosidase inhibitors Gut DPP-4 inhibitors Biguanides

27 27 Mean Change in HbA 1c (%) Placebo + MetRSG 4 mg QD + Met RSG 8 mg QD + Met Compared to Baseline Treatment Effect -1.0* -1.2* Rosiglitazone/Metformin Combination: Additive Glycemic Control vs Metformin Alone *P< vs. metformin

28 Weeks Met + PlaceboMet + pio 30 mg Change From Baseline (% points) Pioglitazone Added to Metformin * P  0.05 vs baseline - 0.8% points P  0.05 vs Metformin + placebo * LOCF * * * * * * HbA 1c.

29 29 Add-on to pioglitazone study 2 Mean Baseline A1C: 8.0%, 8.1% Mean Change in A1C From Baseline, % Sitagliptin A1C Reductions From Baseline When Added to Metformin or Pioglitazone 24-week change from baseline n=224 Metformin sitagliptin –1.0 –0.8 –0.6 0 –1.0 0 Mean Change in A1C From Baseline, % –0.7% Mean Baseline A1C: 8.0% P<0.001* Add-on to metformin study 1 –0.0% Metformin + Placebo Pioglitazone + sitagliptin Pioglitazone + Placebo *Compared with placebo. 1. Charbonnel B et al. Diabetes Care. 2006;29:2638– Rosenstock J et al. Clin Ther. 2006;28:1556–1568. n=453n=174n= % placebo- subtracted result –0.9% –0.4 –0.2 –0.8 –0.6 –0.4 –0.2 –0.2%

30 30 RSG/Met Reductions in A1C in Drug-Naïve Patients Mean change from baseline in A1C (%) at Week 32 RSG/Met METRSG Baseline A1C (%) n= Mean final dose7.2 mg/1799 mg7.7 mg1847 mg. Rosenstock J et al. Diabetes Obes Metab. 2006;8:650–660.  -0.4 P <.001*  -0.6 P <.0001* –2.3% –1.6% –1.8%

31 31 AACE Diabetes Roadmap Guide to therapy base on A1C level Initiation as well as maintaining therapy AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007

32 32 Road Map to Achieve Glycemic Goals: Naïve to Therapy (Type 2) Initial A1C% Achieve ACE Glycemic Goals † ( FPG, PPG, and A1C ) Intervention Continuous Titration of Rx ( months ) If ≤ 6.5% A1C Goal Not Achieved Assess FPG and PPG Initial Therapy Monitor / adjust Rx to maximal effective dose to meet ACE Glycemic Goals Intensify Lifestyle Modification Intensify or combine Rx including incretin mimetic *1 Target: PPG and FPG Monitor / adjust Rx to maximal effective dose to meet ACE Glycemic Goals Combine Therapies 6,7 Intensify Lifestyle Modification Intensify or combine Rx, including incretin mimetic with SU, TZD, and/or metformin Lifestyle Modification Lifestyle Modification If ≤ 6.5% A1C Goal Not Achieved Alternatives Glinides SU (low dose) Prandial insulin 5,8 Preferred: Metformin 4 TZD 10,11,12 AGI DPP-4 Inhibitor Alternatives Prandial insulin 5,8 Premixed insulin preparations 5 Basal insulin analog 9 Metformin Glinides AGI TZD 12 SU DPP-4 Inhibitor + met Colesevelam + met, SU or insulin Revision April 2008 ©2008 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE. 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 Endocr Pract. 2007;13: † ACE Glycemic Goals ≤ 6.5% A1C < 110 mg/dL FPG < 110 mg/dL Preprandial < 140 mg/dL 2-hr PPG *Available as exenatide 1Indicated for patients not at goal despite SU and/or metformin or TZD therapy; incretin mimetic is not indicated for insulin-using patients 4Preferred first agent in most patients 5Analog preparations preferred 6Appropriate for most patients 72 or more agents may be required 8Rapid-acting insulin analog (available as lispro, aspart and glulisine) or regular insulin 9Available as glargine and detemir 10A recent meta-analysis suggests a possible link of rosiglitazone to cardiovascular events; other studies do not confirm or exclude this risk. The FDA has stated “In their entirety, the available data on the risk of myocardial infarction are inconclusive.” 11Cannot be used in NYHA CHF Class 3 or 4 12According to the FDA, rosiglitazone not recommended with insulin

33 Initial A1C% Achieve ACE Glycemic Goals † ( FPG, PPG, and A1C ) Intervention Continuous Titration of Rx ( months ) If ≤ 6.5% A1C Goal Not Achieved Target: FPG and PPG Monitor / adjust Rx to maximal effective dose to meet ACE Glycemic Goals Intensify Lifestyle Modification Intensify or combine Rx including prandial insulin 5,8, incretin mimetic 1, or amylin analog** (with prandial insulin 5,8 ) Target: FPG and PPG Monitor / adjust Rx to maximal effective dose to meet ACE Glycemic Goals Combine Therapies to Address FPG and PPG 7 Combine Therapies to Address FPG and PPG Prandial insulin 5,8 Premixed insulin preparations 5 NPH Other approved combinations Metformin TZD 10,11,12 SU Glinides DPP-4 Inhibitor Basal insulin analog 9 Prandial insulin 5,8 Premixed insulin preparations 5 NPH Other approved combinations Metformin TZD 12 SU Glinides Basal insulin analog 9 If ≤ 6.5% A1C Goal Not Achieved Lifestyle Modification Lifestyle Modification Intensify Lifestyle Modification Initiate or intensify insulin therapy or add incretin mimetic 1 Road Map to Achieve Glycemic Goals: Naïve to Therapy (Type 2) 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 † ACE Glycemic Goals ≤ 6.5% A1C < 110 mg/dL FPG < 110 mg/dL Preprandial < 140 mg/dL 2-hr PPG Endocr Pract. 2007;13: **Available as pramlintide 1Indicated for patients not at goal despite SU and/or metformin or TZD therapy; incretin mimetic is not indicated for insulin-using patients 5Analog preparations preferred 72 or more agents may be required 8Rapid-acting insulin analog (available as lispro, aspart and glulisine) or regular insulin 9Available as glargine and detemir 10A recent meta-analysis suggests a possible link of rosiglitazone to cardiovascular events; other studies do not confirm or exclude this risk. The FDA has stated “In their entirety, the available data on the risk of myocardial infarction are inconclusive.” 11Cannot be used in NYHA CHF Class 3 or 4 12According to the FDA, rosiglitazone not recommended with insulin Revision April 2008 ©2008 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE.

34 34 Lifestyle Modification > 10 Initial A1C% Achieve ACE Glycemic Goals † ( FPG, PPG, and A1C ) Intervention Continuous Titration of Rx ( months ) If ≤ 6.5% A1C Goal Not Achieved Insulin Therapy 2,3 Monitor / adjust Rx to maximal effective dose to meet ACE Glycemic Goals Intensify Lifestyle Modification Basal insulin analog 9 or NPH + prandial insulin 5,8 Premixed insulin preparations 5 Road Map to Achieve Glycemic Goals: Naïve to Therapy (Type 2) 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 † ACE Glycemic Goals ≤ 6.5% A1C < 110 mg/dL FPG < 110 mg/dL Preprandial < 140 mg/dL 2-hr PPG Endocr Pract. 2007;13: For selected patients presenting with an A1C of >10%, certain oral agent combinations may be effective 3Insulin sensitizer (metformin preferred) may be combined with initial insulin therapy 5Analog preparations preferred 8Rapid-acting insulin analog (available as lispro, aspart and glulisine) or regular insulin 9Available as glargine and detemir Revision April 2008 ©2008 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE.

35 35 Current A1C% Current Therapy Intervention 6.5 to 8.5 Continue Lifestyle Modification Monitor / adjust Rx to maintain ACE Glycemic Goals † Monotherapy : Glinides, SU, AGI, metformin, TZD, DPP-4, premixed insulin preparations 1, prandial 2 or basal insulin 3 Continuous Titration of Rx (2-3 months) Combination Therapy: Glinides, SU, DPP-4, AGI, metformin, TZD, colesevelam, incretin mimetic*, premixed insulin preparations 1, prandial 2 or basal insulin 3 Intensify Lifestyle Modification Maximize Combination Therapy Maximize Insulin Therapy Monitor / adjust Rx to maintain ACE Glycemic Goals † Intensify Lifestyle Modification Initiate Combination Therapy Incretin mimetic + metformin and/or TZD Basal 3 or premixed insulin preparations 1 Amylin analog** with prandial insulin 2 Metformin + SU or Glinide Metformin + TZD 4,5 or AGI TZD + SU DPP-4 + Metformin ± SU DPP-4 + TZD Colesevelam + met, SU or insulin Incretin mimetic* + metformin and/or SU Other approved combinations including approved oral agents with insulin 6 If elevated FPG, add or increase basal insulin 3 If elevated PPG, add or increase prandial insulin 2 If elevated FPG and PPG, add or intensify basal 3 + prandial 2 or premixed insulin therapy 1 Combine with approved oral agents 6 Amylin analog** with prandial insulin 2 Add incretin mimetic to patients on SU, TZD, and/or metformin Continuous Titration of Rx (2-3 months) Road Map to Achieve Glycemic Goals: Treated Patients (Type 2) 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 † ACE Glycemic Goals ≤ 6.5% A1C < 110 mg/dL FPG < 110 mg/dL Preprandial < 140 mg/dL 2-hr PPG *Available as exenatide **Available as pramlintide 1Analog preparations preferred 2Prandial insulin (rapid-acting insulin analogs available as lispro, aspart, glulisine, or regular insulin) can be added to any therapeutic intervention at any time to address persistent postprandial hyperglycemia 3Available as glargine and detemir 4A recent meta-analysis suggests a possible link of rosiglitazone to cardiovascular events; other studies do not confirm or exclude this risk. The FDA has stated “In their entirety, the available data on the risk of myocardial infarction are inconclusive.” 5Cannot be used in NYHA CHF Class 3 or 4 6According to the FDA, rosiglitazone not recommended with insulin Endocr Pract. 2007;13: Revision April 2008 ©2008 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE.

36 36 Current A1C% Current Therapy Intervention Intensify Lifestyle Modification Initiate Insulin Therapy (Basal-Bolus) Basal 3 + prandial insulin 2 Premixed insulin preparations 1 Combine with approved oral agents 4 >8.5 Continue Lifestyle Modification Monitor / adjust Rx to maintain ACE Glycemic Goals † Monotherapy or Combination Therapy Continuous Titration of Rx (2-3 months) Road Map to Achieve Glycemic Goals: Treated Patients (Type 2) 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 † ACE Glycemic Goals ≤ 6.5% A1C < 110 mg/dL FPG < 110 mg/dL Preprandial < 140 mg/dL 2-hr PPG Endocr Pract. 2007;13: Analog preparations preferred 2Prandial insulin (rapid-acting insulin analogs available as lispro, aspart, glulisine, or regular insulin) can be added to any therapeutic intervention at any time to address persistent postprandial hyperglycemia 3Available as glargine and detemir 4According to the FDA, rosiglitazone not recommended with insulin Revision April 2008 ©2008 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE.

37 37 Case Study: Mona Female, 60 years old, obese Serum creatinine: 1.4 mg/dL A1C: 6.9% Treatment-naive for diabetes Antihypertensive therapy History of inflammatory bowel disease Recent myocardial infarction Treatment option(s): ? ?

38 38 Road Map to Achieve Glycemic Goals: Naïve to Therapy (Type 2) Initial A1C% Achieve ACE Glycemic Goals † ( FPG, PPG, and A1C ) Intervention Continuous Titration of Rx ( months ) If ≤ 6.5% A1C Goal Not Achieved Assess FPG and PPG Initial Therapy Monitor / adjust Rx to maximal effective dose to meet ACE Glycemic Goals Intensify Lifestyle Modification Intensify or combine Rx including incretin mimetic *1 Target: PPG and FPG Monitor / adjust Rx to maximal effective dose to meet ACE Glycemic Goals Combine Therapies 6,7 Intensify Lifestyle Modification Intensify or combine Rx, including incretin mimetic with SU, TZD, and/or metformin Lifestyle Modification Lifestyle Modification If ≤ 6.5% A1C Goal Not Achieved Alternatives Glinides SU (low dose) Prandial insulin 5,8 Preferred: Metformin 4 TZD 10,11,12 AGI DPP-4 Inhibitor Alternatives Prandial insulin 5,8 Premixed insulin preparations 5 Basal insulin analog 9 Metformin Glinides AGI TZD 12 SU DPP-4 Inhibitor + met Colesevelam + met, SU or insulin Revision April 2008 ©2008 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE. 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 Endocr Pract. 2007;13: † ACE Glycemic Goals ≤ 6.5% A1C < 110 mg/dL FPG < 110 mg/dL Preprandial < 140 mg/dL 2-hr PPG *Available as exenatide 1Indicated for patients not at goal despite SU and/or metformin or TZD therapy; incretin mimetic is not indicated for insulin-using patients 4Preferred first agent in most patients 5Analog preparations preferred 6Appropriate for most patients 72 or more agents may be required 8Rapid-acting insulin analog (available as lispro, aspart and glulisine) or regular insulin 9Available as glargine and detemir 10A recent meta-analysis suggests a possible link of rosiglitazone to cardiovascular events; other studies do not confirm or exclude this risk. The FDA has stated “In their entirety, the available data on the risk of myocardial infarction are inconclusive.” 11Cannot be used in NYHA CHF Class 3 or 4 12According to the FDA, rosiglitazone not recommended with insulin

39 39 Case Study: Nancy Female, 55 years old, obese Serum creatinine: 1.0 mg/dL A1C: 8.5% Treatment-naive for diabetes Antihypertensive therapy Treatment option(s): ? ?

40 Initial A1C% Achieve ACE Glycemic Goals † ( FPG, PPG, and A1C ) Intervention Continuous Titration of Rx ( months ) If ≤ 6.5% A1C Goal Not Achieved Target: FPG and PPG Monitor / adjust Rx to maximal effective dose to meet ACE Glycemic Goals Intensify Lifestyle Modification Intensify or combine Rx including prandial insulin 5,8, incretin mimetic 1, or amylin analog** (with prandial insulin 5,8 ) Target: FPG and PPG Monitor / adjust Rx to maximal effective dose to meet ACE Glycemic Goals Combine Therapies to Address FPG and PPG 7 Combine Therapies to Address FPG and PPG Prandial insulin 5,8 Premixed insulin preparations 5 NPH Other approved combinations Metformin TZD 10,11,12 SU Glinides DPP-4 Inhibitor Basal insulin analog 9 Prandial insulin 5,8 Premixed insulin preparations 5 NPH Other approved combinations Metformin TZD 12 SU Glinides Basal insulin analog 9 If ≤ 6.5% A1C Goal Not Achieved Lifestyle Modification Lifestyle Modification Intensify Lifestyle Modification Initiate or intensify insulin therapy or add incretin mimetic 1 Road Map to Achieve Glycemic Goals: Naïve to Therapy (Type 2) 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 † ACE Glycemic Goals ≤ 6.5% A1C < 110 mg/dL FPG < 110 mg/dL Preprandial < 140 mg/dL 2-hr PPG Endocr Pract. 2007;13: **Available as pramlintide 1Indicated for patients not at goal despite SU and/or metformin or TZD therapy; incretin mimetic is not indicated for insulin-using patients 5Analog preparations preferred 72 or more agents may be required 8Rapid-acting insulin analog (available as lispro, aspart and glulisine) or regular insulin 9Available as glargine and detemir 10A recent meta-analysis suggests a possible link of rosiglitazone to cardiovascular events; other studies do not confirm or exclude this risk. The FDA has stated “In their entirety, the available data on the risk of myocardial infarction are inconclusive.” 11Cannot be used in NYHA CHF Class 3 or 4 12According to the FDA, rosiglitazone not recommended with insulin Revision April 2008 ©2008 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE.

41 41 Case Study: Archie Male, 54 years old, obese Serum creatinine: 0.9 mg/dL A1C: 8.4% Has been receiving metformin 1,000 mg twice a day for past 6 months Treatment option(s): ? ?

42 42 Current A1C% Current Therapy Intervention 6.5 to 8.5 Continue Lifestyle Modification Monitor / adjust Rx to maintain ACE Glycemic Goals † Monotherapy : Glinides, SU, AGI, metformin, TZD, DPP-4, premixed insulin preparations 1, prandial 2 or basal insulin 3 Continuous Titration of Rx (2-3 months) Combination Therapy: Glinides, SU, DPP-4, AGI, metformin, TZD, colesevelam, incretin mimetic*, premixed insulin preparations 1, prandial 2 or basal insulin 3 Intensify Lifestyle Modification Maximize Combination Therapy Maximize Insulin Therapy Monitor / adjust Rx to maintain ACE Glycemic Goals † Intensify Lifestyle Modification Initiate Combination Therapy Incretin mimetic + metformin and/or TZD Basal 3 or premixed insulin preparations 1 Amylin analog** with prandial insulin 2 Metformin + SU or Glinide Metformin + TZD 4,5 or AGI TZD + SU DPP-4 + Metformin ± SU DPP-4 + TZD Colesevelam + met, SU or insulin Incretin mimetic* + metformin and/or SU Other approved combinations including approved oral agents with insulin 6 If elevated FPG, add or increase basal insulin 3 If elevated PPG, add or increase prandial insulin 2 If elevated FPG and PPG, add or intensify basal 3 + prandial 2 or premixed insulin therapy 1 Combine with approved oral agents 6 Amylin analog** with prandial insulin 2 Add incretin mimetic to patients on SU, TZD, and/or metformin Continuous Titration of Rx (2-3 months) Road Map to Achieve Glycemic Goals: Treated Patients (Type 2) 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 † ACE Glycemic Goals ≤ 6.5% A1C < 110 mg/dL FPG < 110 mg/dL Preprandial < 140 mg/dL 2-hr PPG *Available as exenatide **Available as pramlintide 1Analog preparations preferred 2Prandial insulin (rapid-acting insulin analogs available as lispro, aspart, glulisine, or regular insulin) can be added to any therapeutic intervention at any time to address persistent postprandial hyperglycemia 3Available as glargine and detemir 4A recent meta-analysis suggests a possible link of rosiglitazone to cardiovascular events; other studies do not confirm or exclude this risk. The FDA has stated “In their entirety, the available data on the risk of myocardial infarction are inconclusive.” 5Cannot be used in NYHA CHF Class 3 or 4 6According to the FDA, rosiglitazone not recommended with insulin Endocr Pract. 2007;13: Revision April 2008 ©2008 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE.

43 43 Clinical Considerations Combining therapeutic agents with different modes of action may be advantageous Use of insulin sensitizers such as metformin and /or thiazolidinediones as part of the therapeutic regimen in most patients unless contraindicated or intolerance to these agents has been demonstrated Metformin, thiazolidinediones, and incretin mimetics do not cause hypoglycemia: when used in combination with secretagogues or insulin, these medications may need to be adjusted as blood glucose levels declined AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007

44 44 Clinical Considerations The weight gain associated with thiazolidinediones in some patient may be partly offset by combination therapy with metformin Carefully assess postprandial glucose levels if the A1C level is elevated and preprandial blood glucose measurements are at target levels INDIVIDUALIZE TREATMENT REGIMENS! AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007


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