1. Glycemic Management in Type 2 Diabetes 1

2. 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.

3. Glycemic Management in Type 2 Diabetes Therapeutic Lifestyle Change 3

4. 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.

5. 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

6. 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.

7. ≥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.

8. Glycemic Management in Type 2 Diabetes Antihyperglycemic Therapy 8

9. 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.

10. 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.

11. 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.

12. 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<0.5~0.5-2.5~3-5  Can be injected 0-15 min before a meal  Less risk of postprandial hypoglycemia compared to regular insulin Glulisine Lispro * Exhibits a peak at higher dosages. † Dose-dependent. Moghissi E, et al. Endocr Pract. 2013;Feb 20:1-33. [Epub ahead of print].

13. Combination Agents Available for the Treatment of Type 2 Diabetes ClassAdded AgentAvailable as Metformin + DPP-4 inhibitor AlogliptinKazano LinagliptinJentadueto SitagliptinJanumet Metformin + glinideRepaglinidePrandimet Metformin + sulfonylurea GlipizideMetaglip and generic GlyburideGlucovance and generic Metformin + thiazolidinedione PioglitazoneACTOplus Met Rosiglitazone*Avandamet Thiazolidinedione + DPP-4 inhibitor Pioglitazone + alogliptin Oseni Thiazolidinedione + sulfonylurea PioglitazoneDuetact Rosiglitazone*Avandaryl *Use restricted due to increased risk of myocardial infarction (MI) 13

14. First Principles of the AACE/ACE T2DM Algorithm Avoid hypoglycemia Avoid weight gain Consider all medication options Recognize that acquisition cost is not the total cost of a drug Stratify therapy selection by A1C Recognize that postprandial glucose is an important target Rodbard HW, et al. Endocr Pract. 2009;15:540-559 14

15. Secondary Principles of AACE/ACE T2DM Algorithm Adherence is improved by –Ease of use –Minimal side effects Improved  -cell performance over a longer period is possible Multiple combinations are required Rodbard HW, et al. Endocr Pract. 2009;15:540-559 15

16. 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

17. *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

18. 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

19. 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

20. 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

21. 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

22. 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 (<100 mg/dL for most patients) Decrease dosage if FPG declines below a threshold specified for individual patient 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 (<100 mg/dL for most patients) Decrease dosage if FPG declines below a threshold specified for individual patient *Under FDA review as of October 2012. Rodbard HW, et al. Endocr Pract. 2009;15:540-559. Basal insulin analogues (detemir, degludec,* or glargine) are strongly preferred over human NPH insulin

23. 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

24. 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)

25. 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

26. A1C goal ≤6.5% may not be appropriate for all patients For patients with diabetes and A1C <6.5%, pharmacologic therapy may still be considered If A1C goal is not achieved, intensify therapy (if it can be done safely) If A1C is <8.5%, combination therapy with agents that cause hypoglycemia should be used with caution –Decrease dose of secretagogue by 50% when added to GLP-1 or DPP-4 If A1C ≥8.5% in patients on dual therapy, consider use of insulin –Discontinue insulin secretagogue with multi-dose insulin –Consider use of pramlintide with prandial insulin Rodbard HW, et al. Endocr Pract. 2009;15:540-559. AACE/ACE T2DM Algorithm: Special Considerations and Caveats 26

27. 27 ADA/EASD T2DM Treatment Algorithm Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.

28. ADA/EASD T2DM Treatment Algorithm: Sequential Insulin Strategies Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379. 28

29. Common Principles in AACE/ACE and ADA/EASD T2DM Treatment Algorithms Individualize glycemic goals based on patient characteristics Promptly intensify antihyperglycemic therapy to maintain blood glucose at individual targets –Combination therapy necessary for most patients –Base choice of agent(s) on individual patient medical history, behaviors and risk factors, ethno-cultural background, and environment Insulin eventually necessary for many patients SMBG vital for day-to-day management of blood sugar –All patients using insulin –Many patients not using insulin 29 Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379. Rodbard HW, et al. Endocr Pract. 2009;15:540-559.

30. Pipeline Classes and Agents (2012) Class Phase of Development AgentsDescription Dual peroxisome proliferator activated receptor  -  (PPAR  -  ) agonist Phase 3 Aleglitazar Improve insulin sensitivity in the periphery as well as lipid profiles Approved agents may reduce both cardiovascular risks and potential for diabetes complications Short-acting GLP-1 receptor agonistLixisenatideHuman-derived molecule with effects similar to exenatide Long-acting GLP-1 receptor agonists Phase 3 Albiglutide Taspoglutide Effects probably similar to currently available GLP-1 receptor agonists Longer duration of action will permit longer intervals between injections Insulin Phase 3 Degludec Ultra-long-acting basal insulin (half-life ~25 hours) with low within-subject variability and potential for reduced incidence of hypoglycemia DegludecPlus Premixed insulin containing degludec plus aspart, providing both fasting and postprandial glucose control Salicylates Phase 3 Salsalate Generically available anti-inflammatory medication currently approved for treatment of arthritis; inhibits activity of NF-  B, an inflammatory factor Sodium-dependent glucose cotransporter 2 (SGLT-2) inhibitors Phase 3 Canagliflozin Dapagliflozin Empagliflozin Tofogliflozin Act in the kidney Reduce hyperglycemia by inhibiting glucose reabsorption into the bloodstream from the renal filtrate, increasing urinary excretion of glucose 11  -Hydroxysteroid dehydrogenase type 1 (11  HSD-1) inhibitors Phase 2 INCB13739 RG4929 Inhibit 11  HSD-1 mediated conversion of low-activity cortisone to cortisol, which is primarily produced in the liver and adipose tissue May lessen stress-induced obesity, improve insulin sensitivity, enhance insulin-secretory responsiveness, and improve glucose tolerance in patients with metabolic syndrome and/or type 2 diabetes 30 Bakris GL, et al. Kidney Int. 2009;75:1272-1277; Calado J, et al. Kidney Int Suppl. 2011:S7-S13; Garber AJ. Expert Opin Investig Drugs. 2012;21:45-57; Goldfine AB, et al. Ann Intern Med. 2010;152:346-357; King A. J Fam Pract. 2012;61:S28-S31; Tahrani AA, et al. Lancet. 2011;378:182-197; Tahrani AA, et al. Lancet. 2012;379:1465-1467.

31. Glycemic Management in Type 2 Diabetes Technology for Type 2 Diabetes Management 31

32. Noninsulin Users Introduce at diagnosis Personalize frequency of testing Use SMBG results to inform decisions about whether to target FPG or PPG for any individual patient Insulin Users All patients using insulin should test glucose –≥2 times daily –Before any injection of insulin More frequent SMBG (after meals or in the middle of the night) may be required –Frequent hypoglycemia –Not at A1C target SMBG in Type 2 Diabetes: AACE/ACE Recommendations 32 Testing positively affects glycemia in T2DM when the results are used to: Modify behavior Modify pharmacologic treatment Testing positively affects glycemia in T2DM when the results are used to: Modify behavior Modify pharmacologic treatment SMBG, self-monitoring of blood glucose. Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

33. Active control group (n=227) Structured testing group (n=256) 7.2 Baseline 7.4 7.6 7.8 8.0 8.2 8.4 8.6 8.8 9.0 M1M3M6M9M12 -0.3% (P=0.04) Adjusted Mean A1C (%) SMBG in Noninsulin Using Patients With T2DM ACG, active cotnrol group; STG, structured testing group. Polonsky WH, et al. Diabetes Care. 2011;34:262-267. ACG 8.9% (0.08) 8.7% (0.1) 8.2% (0.1) 7.9% (0.1) 8.0% (0.1) STG 8.9% (0.07) 8.5% (0.09) 7.9% (0.09) 7.6% (0.09) 7.7% (0.09) 33

34. Absolutely insulin-deficient Take 4 or more insulin injections a day Assess blood glucose levels 4 or more times daily Motivated to achieve tighter glucose control Mastery of carbohydrate counting, insulin correction, and adjustment formulas Ability to troubleshoot problems related to pump operation and plasma glucose levels Stable life situation Frequent contact with members of their healthcare team, in particular their pump- supervising physician CSII in Type 2 Diabetes: Patient Candidates CSII, continuous subcutaneous insulin infusion. Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. 34

35. Glycemic Management in Type 2 Diabetes Surgical Intervention 35

36. Surgical Intervention in Type 2 Diabetes 36 Schauer PR, et al. N Engl J Med. 2012;366:1567-1576. Months 3.5 2.5 1.5 0.5 0.0 1.0 2.0 3.0 Baseline 3 6 9 12 Average no. diabetes medications P<0.001 -2 -6 -10 -12 -8 -4 0 Baseline 3 6 9 12  BMI (kg/m 2 ) P<0.001 20 -40 -100 -140 -160 -120 -60 -20 -80 0 Baseline 3 6 9 12  FPG (mg/dL) P=0.02 P<0.001 0.0 1.0 2.0 3.0 3.5 2.5 1.5 0.5 Baseline 3 6 9 12  A1C (%) P<0.001 Intensive medical therapySleeve gastrectomy Roux-en-Y gastric bypass

37. Glycemic Management in Type 2 Diabetes Safety Concerns: Hypoglycemia 37

38. Type 2 Diabetes Pathophysiology: Origins of Hypoglycemia Cryer PE. Am J Physiol. 1993; 264(2 Pt 1):E149-E155. Defect β-cells Increased insulin availability due to use of secretagogues or exogenous insulin Liver Suppressed hepatic glucose production due to impaired counter- regulatory response Skeletal muscleIncreased glucose uptake due to exercise α-cellsSuppressed glucagon due to impaired counter-regulatory response BrainHypoglycemia unawareness 38

39. Hypoglycemia: Risk Factors Patient Characteristics Older age Female gender African American ethnicity Longer duration of diabetes Neuropathy Renal impairment Previous hypoglycemia Behavioral and Treatment Factors Missed meals Elevated A1C Insulin or sulfonylurea therapy Miller ME, et al. BMJ. 2010 Jan 8;340:b5444. doi: 10.1136/bmj.b5444. 39

40. 0 10 20 30 40 50 60 70 80 90 100 Blood Glucose (mg/dL) Decreased insulin secretion Increased glucagon, epinephrine, ACTH, cortisol, and growth hormone Palpitation, sweating Decreased cognition, hunger Aberrant behavior Seizures, coma Neuronal cell death Moghissi E, et al. Endocr Pract. 2013;Feb 20:1-33. [Epub ahead of print]. Symptoms and Signs with Progressive Hypoglycemia

41. Hypoglycemia: Clinical Consequences Acute Symptoms (sweating, irritability, confusion) Accidents Falls Long-term Recurrent hypoglycemia and hypoglycemia unawareness Refractory diabetes Dementia (elderly) CV events –Cardiac autonomic neuropathy –Cardiac ischemia –Fatal arrhythmia –Angina Cryer PE, et al. Diabetes Care. 2003;26:1902-1912. ADA. Diabetes Care. 2013;36(suppl 1):S11-S66. Zammit NN, et al. Diabetes Care. 2005;28:2948-2961. 41

42. Treatment of Hypoglycemia: AACE/ACE Recommendations Cryer PE, et al. Diabetes Care. 2003;26:1902-1912. Blood Glucose Level Classification Typical Signs and Symptoms Treatment ~50-60Mild hypoglycemia  Neurogenic: palpitations, tremor, hunger, sweating, anxiety, paresthesia  Neuroglycopenic: behavioral changes, emotional lability, difficulty thinking, confusion  Consume glucose-containing foods (fruit juice, soft drink, crackers, milk, glucose tablets); avoid foods also containing fat  Repeat glucose intake if SMBG result remains low after 15 minutes  Consume meal or snack after SMBG has returned to normal to avoid recurrence <50Moderate hypoglycemia Severe hypoglycemia  Severe confusion, unconsciousness, seizure, coma, death  Requires help from another individual  Glucagon injection, delivered by family member or other close associate  Victim should be taken to hospital for evaluation and treatment after any severe episode 42

43. Elements of Hypoglycemia Prevention Set appropriate glycemic targets for individual patients  More stringent goals: young, newly diagnosed, no comorbidities, no micro- or macrovascular disease, strong and effective self-care skills  Less stringent goals: older, limited life expectancy, history of hypoglycemia, longer disease duration, established comorbidities, established vascular disease, limited self- care skills Educate patients  Signs and symptoms of hypoglycemia  Dietary education for improved glycemic control and appreciation of triggers for hypoglycemia  Avoiding missed or delayed meals  Appropriate self-treatment  Understanding of hypoglycemia unawareness  Importance of reporting hypoglycemia Use self-monitoring of blood glucose  Patient education: technique and action  Observation of patient’s procedure and reaction  Patient access to providers for purposes of reporting results and for providing guidance  Provider reaction to results increases effectiveness of SMBG Hold a high index of suspicion for hypoglycemia  Understand patients may not report “typical” symptoms  When hypoglycemia is suspected, adjust therapy  Consider use of continuous glucose monitoring to detect unrecognized hypoglycemia Choose appropriate therapy  Use agents with a low risk of hypoglycemia  Be aware of additive effects of combination therapies on hypoglycemia risk  Recognize that long-term costs of hypoglycemia may offset the cost of using older, less physiologic medications 43 Moghissi E, et al. Endocr Pract. 2013;Feb 20:1-33. [Epub ahead of print].

44. GLP-1 receptor agonists DPP-4 inhibitors TZDs Insulin (basal, basal-plus, premixed) Sulfonylureas Metformin Less Hypoglycemia More Hypoglycemia Initial TreatmentAdditional Treatment Moghissi E, et al. Endocr Pract. 2013;Feb 20:1-33. [Epub ahead of print]. Hypoglycemia Risk With Antihyperglycemic Agents Added to Metformin

45. Percentage of Patients Treated in 1 Year 0 1% 2% 3% 4% 5% 6% Mixtures, Rapid-acting, Basal-bolus Insulin Basal Sulfonylureas DPP-4 inhibitors, GLP-1 receptor agonists, Metformin, TZDs Meglinitides Frequency of Severe Hypoglycemia With Antihyperglycemic Agents Moghissi E, et al. Endocr Pract. 2013;Feb 20:1-33. [Epub ahead of print].

46. Increasing rates of hypoglycemia Most frequent Prandial and premixed More frequent Basal + Less frequent Basal only Human insulin Analogue insulins Premixed (70/30, 75/25) Basal plus 2-3 prandial Basal plus one prandial NPH Basal analogues (glargine, detemir) Pipeline basal analogues (degludec, pegylated lispro) Moghissi E, et al. Endocr Pract. 2013;Feb 20:1-33. [Epub ahead of print]. Relative Rates of Severe Hypoglycemia with Insulin

47. Glycemic Management in Type 2 Diabetes Safety Concerns: Weight 47

48. Antidiabetic Agents and Weight Risk of additional weight gain must be balanced against the benefits of the agent –Sulfonylureas may negate weight loss benefits of GLP-1 receptor agonists or metformin –Insulin should not be withheld because of the risk of weight gain Weight GainWeight Neutral or Weight Loss Glinides Insulin Sulfonylureas Thiazolidinediones  -Glucosidase inhibitors Bromocriptine Colesevelam DPP-4 inhibitors GLP-1 receptor agonists Metformin Pramlintide Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379. Rodbard HW, et al. Endocr Pract. 2009;15:540-559. Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. 48

49. Glycemic Management in Type 2 Diabetes Safety Concerns: Cancer Risk 49

50. Insulin and Cancer Risk 50 StudyHazard Ratio (95% CI) Outcome Reduction With an Initial Glargine Intervention (ORIGIN) N=12,537; prospective RCT Median follow-up: 6.2 years Any cancer: 1.00 (0.88-1.13); P=0.97 Death from cancer: 0.94 (0.77-1.15); P=0.52 Northern European Database Study N=447,821; observational Mean follow-up: Glargine users: 3.1 years Other insulin users: 3.5 years Breast cancer (women): 1.12 (0.99-1.27) Prostate cancer (men): 1.11 (1.00-1.24) Colorectal cancer (men and women): 0.86 (0.76-0.98) Kaiser-Permanente Collaboration N=115,000; observational Median follow-up: Glargine users: 1.2 years NPH users: 1.4 years Breast cancer (women): 1.0 (0.9-1.3) Prostate cancer (men): 0.7 (0.6-0.9) Colorectal cancer (men and women): 1.00 (0.8-1.2) All cancers (men and women): 0.9 (0.9-1.0) MedAssurant Database Study N=52,453; observational Mean follow-up: Glargine users: 1.2 years NPH users: 1.1 years No increased risk for breast cancer ORIGIN Trial Investigators. N Engl J Med. 2012;367:319-328. Kirkman MS, et al. Presented at the American Diabetes Association 72 nd Scientific Sessions. June 11, 2012. Session CT-SY13. Philadelphia, PA.

51. Glycemic Management in Type 2 Diabetes Special Populations and Situations 51

52. Management Considerations for Elderly Patients with Diabetes 52 Bourdel Marchasson I, et al. J Nutr Health Aging. 2009;13:685-691. Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. Schwartz AV, et al. Diabetes Care. 2008;31:391-396. Zammitt NN, Frier BM. Diabetes Care. 2005;28:2948-2961. Increased risk of and from falling Impaired vision Reduced strength and stamina Sensitivity to medication side effects Frailty Susceptibility to hypoglycemia Impaired vision Reduced strength and stamina Sensitivity to medication side effects Frailty Susceptibility to hypoglycemia Hypoglycemia unawareness and recurrent hypoglycemia Impaired counter- regulatory mechanisms Impaired capacity, understanding, and/or motivation for proper self-care Cognitive decline and dementia Depression Impaired vision Cognitive decline and dementia Depression Impaired vision Other complicating factors Diminished kidney function Urinary incontinence Status of social support and/or caregiver Drug-drug interactions Diminished kidney function Urinary incontinence Status of social support and/or caregiver Drug-drug interactions Consider risks before prescribing: Sulfonylureas and glinides (hypoglycemia risk) Thiazolidinediones (fracture risk) Metformin (risk of lactic acidosis with decreased kidney function) Sulfonylureas and glinides (hypoglycemia risk) Thiazolidinediones (fracture risk) Metformin (risk of lactic acidosis with decreased kidney function) Consider when establishing treatment goals Patient overall health and well-being Self-care capacities Social/family support Patient overall health and well-being Self-care capacities Social/family support

53. Risk Considerations for Religious/Cultural Fasting Risk CategoryFeatures Low  Glycemia well-controlled with antihyperglycemic agent that does not cause hypoglycemia (eg, metformin, thiazolidinedione, DPP-4 inhibitor, GLP-1 receptor agonist)  Otherwise healthy Moderate  Glycemia well-controlled with glinides High  Moderate hyperglycemia (A1C 7.5-9.0%), renal insufficiency, cardiovascular complications, and/or other comorbid conditions  Living alone, especially if taking sulfonylureas, insulin, or drugs that affect mentation  Elderly, especially with poor health Very high  History of recurrent hypoglycemia, hypoglycemia unawareness, or episode of severe hypoglycemia within 3 months prior to Ramadan  Poor glycemic control  Ketoacidosis or hyperosmotic hyperglycemic coma within 3 months prior to Ramadan  Acute illness or chronic dialysis  Intense physical labor  Pregnancy 53 Al-Arouj M, et al. Diabetes Care. 2005;28:2305-2311. Main Risks of Fasting Hypoglycemia Hyperglycemia Diabetic ketoacidosis Dehydration and thrombosis

54. Glycemic Management During Religious/Cultural Fasting 54 Al-Arouj M, et al. Diabetes Care. 2005;28:2305-2311. Frequent glucose monitoring—break fast immediately if patient has: –Hypoglycemia SMBG <70 mg/dL while taking insulin or sulfonylureas SMBG <60 mg/dL while on other therapies –Hyperglycemia: >300 mg/dL Healthful eating before and after each fasting period –Complex carbohydrates prior to fast –Avoid ingesting high-carbohydrate, high-fat foods when breaking fast Avoid excessive physical activity but maintain normal exercise routines Avoid fasting while ill