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Glycemic Management in Type 2 Diabetes 1

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AACE Comprehensive Care Plan Disease management from a multidisciplinary team Antihyperglycemic pharmacotherapy Comprehensive diabetes self-education for the patient Therapeutic lifestyle change Comprehensive Care Plan 2 Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

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Glycemic Management in Type 2 Diabetes Therapeutic Lifestyle Change 3

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Components of Therapeutic Lifestyle Change Healthful eating Sufficient physical activity Sufficient sleep Avoidance of tobacco products Limited alcohol consumption Stress reduction 4 Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

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AACE Healthful Eating Recommendations 5 Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. TopicRecommendation General eating habits Regular meals and snacks; avoid fasting to lose weight Plant-based diet (high in fiber, low calories, low glycemic index, high in phytochemicals/antioxidants) Understand Nutrition Facts Label information Incorporate beliefs and culture into discussions Informal physician-patient discussions Use mild cooking techniques instead of high-heat cooking Carbohydrate Understand health effects of the 3 types of carbohydrates: sugars, starch, and fiber Target 7-10 servings per day of healthful carbohydrates (fresh fruits and vegetables, pulses, whole grains) Lower-glycemic index foods may facilitate glycemic control:* multigrain bread, pumpernickel bread, whole oats, legumes, apple, lentils, chickpeas, mango, yams, brown rice Fat Eat healthful fats: low-mercury/low-contaminant-containing nuts, avocado, certain plant oils, fish Limit saturated fats (butter, fatty red meats, tropical plant oils, fast foods) and trans fats Use no- or low-fat dairy products Protein Consume protein from foods low in saturated fats (fish, egg whites, beans) Avoid or limit processed meats Micronutrients Routine supplementation not necessary except for patients at risk of insufficiency or deficiency Chromium; vanadium; magnesium; vitamins A, C, and E; and CoQ10 not recommended for glycemic control *Insufficient evidence to support a formal recommendation to educate patients that sugars have both positive and negative health effects

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AACE Medical Nutritional Therapy Recommendations Consistency in day-to-day carbohydrate intake Adjusting insulin doses to match carbohydrate intake (eg, use of carbohydrate counting) Limitation of sucrose-containing or high- glycemic index foods Adequate protein intake Heart-healthy diets Weight management Exercise Increased glucose monitoring 6 Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

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150 minutes per week of moderate-intensity exercise Flexibility and strength training Aerobic exercise (eg, brisk walking) Start slowly and build up gradually Evaluate for contraindications and/or limitations to increased physical activity before patient begins or intensifies exercise program Develop exercise recommendations according to individual goals and limitations AACE Physical Activity Recommendations 7 Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

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Glycemic Management in Type 2 Diabetes Antihyperglycemic Therapy 8

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Noninsulin Agents Available for Treatment of Type 2 Diabetes ClassPrimary Mechanism of ActionAgentAvailable as -Glucosidase inhibitors Delay carbohydrate absorption from intestine AcarbosePrecose or generic MiglitolGlyset Amylin analogue Decrease glucagon secretion Slow gastric emptying Increase satiety PramlintideSymlin Biguanide Decrease HGP Increase glucose uptake in muscle MetforminGlucophage or generic Bile acid sequestrant Decrease HGP? Increase incretin levels? ColesevelamWelChol DPP-4 inhibitors Increase glucose-dependent insulin secretion Decrease glucagon secretion AlogliptinNesina LinagliptinTradjenta SaxagliptinOnglyza SitagliptinJanuvia Dopamine-2 agonist Activates dopaminergic receptors BromocriptineCycloset 9 HGP, hepatic glucose production. Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.

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Noninsulin Agents Available for Treatment of Type 2 Diabetes ClassPrimary Mechanism of ActionAgentAvailable as Glinides Increase insulin secretion NateglinideStarlix or generic RepaglinidePrandin GLP-1 receptor agonists Increase glucose-dependent insulin secretion Decrease glucagon secretion Slow gastric emptying Increase satiety ExenatideByetta Exenatide XRBydureon LiraglutideVictoza Sulfonylureas Increase insulin secretion GlimepirideAmaryl or generic GlipizideGlucotrol or generic Glyburide Dia eta, Glynase, Micronase, or generic Thiazolidinediones Increase glucose uptake in muscle and fat Decrease HGP PioglitazoneActos Rosiglitazone*Avandia *Use restricted due to increased risk of myocardial infarction (MI) 10 HGP, hepatic glucose production. Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.

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Insulins Available for the Treatment of Type 2 Diabetes ClassPrimary Mechanism of ActionAgentAvailable as Basal Increase glucose uptake Decrease HGP DetemirLevemir GlargineLantus Neutral protamine Hagedorn (NPH) Generic Prandial AspartNovoLog GlulisineApidra LisproHumalog Regular humanHumulin, generic Premixed Biphasic aspartNovoLog Mix Biphasic lisproHumalog Mix 11 Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.

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Pharmacokinetics of Insulin 12 AgentOnset (h)Peak (h)Duration (h)Considerations Basal NPH2-44-1010-16Greater risk of nocturnal hypoglycemia compared to insulin analogues Glargine~1-4No pronounced peak* Up to 24 hours Less nocturnal hypoglycemia compared to NPH Detemir Prandial Regular~0.5-1~2-3Up to 8 Must be injected 30-45 min before a meal Injection with or after a meal could increase risk for hypoglycemia Aspart

Stratify treatment based on initial A1C level Initial monotherapy for A1C 6.5% to 7.5% Initial dual therapy for A1C 7.6% to 9.0% Initial triple therapy or insulin for A1C >9.0% Monitor A1C carefully and intensify therapy at 2- to 3- month intervals if A1C goal not achieved Monotherapy dual therapy Dual therapy triple therapy or insulin oral agents Combine agents with different mechanisms of action Overview of AACE/ACE T2DM Algorithm Rodbard HW, et al. Endocr Pract. 2009;15:540-559 16

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*The abbreviations used here correspond to those used on the algorithm (Fig. 1). **The term glinide includes both repaglinide and nateglinide. Benefits are classified according to major effects on fasting glucose, postprandial glucose, and nonalcoholic fatty liver disease (NAFLD). Eight broad categories of risks are summarized. The intensity of the background shading of the cells reflects relative importance of the benefit or risk.* Available at www.aace.com/pub AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE 17

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A1C 6.5 7.5% ** Monotherapy MET + GLP-1 or DPP4 1 TZD 2 Glinide or SU 5 TZD + GLP-1 or DPP4 1 MET + Colesevelam AGI 3 2 - 3 Mos. *** Dual Therapy MET + GLP-1 or DPP4 1 + TZD 2 Glinide or SU 4,7 A1C > 9.0% No Symptoms Drug Naive Under Treatment INSULIN Other Agent(s) 6 Symptoms INSULIN Other Agent(s) 6 INSULIN Other Agent(s) 6 Triple Therapy AACE/ACE Algorithm for Glycemic Control Committee Cochairpersons: Helena W. Rodbard, MD, FACP, MACE Paul S. Jellinger, MD, MACE Zachary T. Bloomgarden, MD, FACE Jaime A. Davidson, MD, FACP, MACE Daniel Einhorn, MD, FACP, FACE Alan J. Garber, MD, PhD, FACE James R. Gavin III, MD, PhD George Grunberger, MD, FACP, FACE Yehuda Handelsman, MD, FACP, FACE Edward S. Horton, MD, FACE Harold Lebovitz, MD, FACE Philip Levy, MD, MACE Etie S. Moghissi, MD, FACP, FACE Stanley S. Schwartz, MD, FACE * May not be appropriate for all patients ** For patients with diabetes and A1C < 6.5%, pharmacologic Rx may be considered *** If A1C goal not achieved safely Preferred initial agent 1DPP4 if PPG and FPG or GLP-1 if PPG 2TZD if metabolic syndrome and/or nonalcoholic fatty liver disease (NAFLD) 3AGI if PPG 4Glinide if PPG or SU if FPG 5Low-dose secretagogue recommended 6a)Discontinue insulin secretagogue with multidose insulin b)Can use pramlintide with prandial insulin 7Decrease secretagogue by 50% when added to GLP-1 or DPP-4 8If A1C < 8.5%, combination Rx with agents that cause hypoglycemia should be used with caution 9If A1C > 8.5%, in patients on Dual Therapy, insulin should be considered MET + GLP-1 or DPP4 1 SU 7 TZD 2 GLP-1 or DPP4 1 TZD 2 A1C 7.6 9.0% Dual Therapy 8 2 - 3 Mos. *** Triple Therapy 9 INSULIN Other Agent(s) 6 MET + GLP-1 or DPP4 1 or TZD 2 SU or Glinide 4,5 MET + GLP-1 or DPP4 1 + TZD 2 GLP-1 or DPP4 1 + SU 7 TZD 2 MET DPP4 1 GLP-1TZD 2 AGI 3 Available at www.aace.com/pub AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE 18

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A1C 6.5 7.5% ** Monotherapy MET+ GLP-1 or DPP4 1 TZD 2 Glinide or SU 5 TZD+GLP-1 or DPP4 1 MET+ Colesevelam AGI 3 2 - 3 Mos. *** Dual Therapy MET + GLP-1 or DPP4 1 + TZD 2 Glinide or SU 4,7 INSULIN Other Agent(s) 6 Triple Therapy MET DPP4 1 GLP-1TZD 2 AGI 3 2 - 3 Mos. *** *** If A1C goal not achieved safely Preferred initial agent 1DPP4 if PPG and FPG or GLP-1 if PPG 2TZD if metabolic syndrome and/or nonalcoholic fatty liver disease (NAFLD) 3AGI if PPG 4Glinide if PPG or SU if FPG 5Low-dose secretagogue recommended 6a)Discontinue insulin secretagogue with multidose insulin b)Can use pramlintide with prandial insulin 7Decrease secretagogue by 50% when added to GLP-1 or DPP-4 Available at www.aace.com/pub AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE LIFESTYLE MODIFICATION AACE/ACE DIABETES ALGORITHM FOR GLYCEMIC CONTROL 19

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MET+ GLP-1 or DPP4 1 + TZD 2 GLP-1 or DPP4 1 + SU 7 TZD 2 A1C 7.6 9.0% Available at www.aace.com/pub AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE Dual Therapy 8 MET+ GLP-1 or DPP4 1 or TZD 2 SU or Glinide 4,5 2 - 3 Mos. *** Triple Therapy 9 2 - 3 Mos. *** INSULIN Other Agent(s) 6 *** If A1C goal not achieved safely Preferred initial agent 1DPP4 if PPG and FPG or GLP-1 if PPG 2TZD if metabolic syndrome and/or nonalcoholic fatty liver disease (NAFLD) 4Glinide if PPG or SU if FPG 5Low-dose secretagogue recommended 6a)Discontinue insulin secretagogue with multidose insulin b)Can use pramlintide with prandial insulin 7Decrease secretagogue by 50% when added to GLP-1 or DPP-4 8If A1C < 8.5%, combination Rx with agents that cause hypoglycemia should be used with caution 9 If A1C > 8.5%, in patients on Dual Therapy, insulin should be considered LIFESTYLE MODIFICATION AACE/ACE DIABETES ALGORITHM FOR GLYCEMIC CONTROL 20

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No Symptoms Drug Naive Under Treatment Symptoms MET+ GLP-1 or DPP4 1 SU 7 TZD 2 GLP-1 or DPP4 1 TZD 2 A1C > 9.0% Available at www.aace.com/pub AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE INSULIN Other Agent(s) 6 INSULIN Other Agent(s) 6 1DPP4 if PPG and FPG or GLP-1 if PPG 2TZD if metabolic syndrome and/or nonalcoholic fatty liver disease (NAFLD) 6a)Discontinue insulin secretagogue with multidose insulin b)Can use pramlintide with prandial insulin 7Decrease secretagogue by 50% when added to GLP-1 or DPP-4 LIFESTYLE MODIFICATION AACE/ACE DIABETES ALGORITHM FOR GLYCEMIC CONTROL 21

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Basal Insulin Therapy in T2DM: AACE/ACE Recommendations Initiate insulin treatment by adding a long-acting basal formulation to existing noninsulin agents 22 Relatively peakless time-action curves Greater day- to-day consistency Lower risk of hypoglycemia Start with 10 U or 0.1-0.2 U/kg per day at bedtime Slowly titrate by 1-3 U every 2-3 days until FPG reaches the desired target (

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Prandial Insulin Therapy in T2DM: AACE/ACE Recommendations Add prandial insulin when A1C levels remain high despite optimal control of FPG with basal insulin noninsulin agents Basal-bolus insulin therapy is flexible and is recommended for intensive insulin therapy Premixed insulin analogues Consider for patients with adherence problems Lack dosage flexibility and may increase risk of hypoglycemia 23 Rodbard HW, et al. Endocr Pract. 2009;15:540-559. Faster onset of action Faster offset of action Lower risk of hypoglycemia Rapid-acting insulin analogues are preferred over regular human insulin

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Early Insulin Use in Type 2 Diabetes Offers No Benefits Over Standard Approaches 24 ORIGIN Trial Investigators. N Engl J Med. 2012;367:319-328. Outcome Reduction With an Initial Glargine Intervention CV risk factors + prediabetes or T2DM (N=12,537) Outcome Reduction With an Initial Glargine Intervention CV risk factors + prediabetes or T2DM (N=12,537)

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Metformin is the preferred initial agent for most patients DPP-4 inhibitors are preferred if both PPG and FPG are elevated GLP-1 agonists are preferred if the principal problem is elevated PPG TZDs can be used to treat patients with metabolic syndrome and/or nonalcoholic fatty liver disease (NAFLD) AGIs are useful for treatment of elevated PPG Glinides can be useful for treatment of elevated PPG SUs may be useful if major problem is elevated FPG Colesevelam may be useful for patients near A1C goal but needing additional LDL-C control AACE/ACE T2DM Algorithm: Special Considerations and Caveats Rodbard HW, et al. Endocr Pract. 2009;15:540-559. 25

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A1C goal 6.5% may not be appropriate for all patients For patients with diabetes and A1C