1. Type 2 Diabetes Glucose Management Goals 1

2. AACE Comprehensive Diabetes Care: Glucose Goals ParameterTreatment Goal for Nonpregnant Adults A1C (%)Individualize based on age, comorbidities, and duration of disease* ≤6.5 for most Closer to normal for healthy Less stringent for “less healthy” FPG (mg/dL)<110 2- hour PPG (mg/dL)<140 Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. 2 *Considerations include Residual life expectancy Duration of T2DM Presence or absence of microvascular and macrovascular complications CVD risk factors Comorbid conditions Risk for severe hypoglycemia Patient’s psychological, social, and economic status

3. Well-Recognized Risks for Hypoglycemia in T2DM Use of insulin secretagogues and insulin therapy in any of the following settings: –Missed or irregular meals –Advanced age –Longer duration of diabetes –Impaired awareness of hypoglycemia –Exercise –Taking greater than the prescribed medication dose –Excessive alcohol intake –Preexisting impairment, or sudden worsening, of renal or hepatic function Less well-recognized risks: female sex, African-American race, less education (ACCORD) 3 Amiel SA, et al. Diabet Med. 2008;25:245-254. ADA. Diabetes Care. 2005;28:1245-1249.

4. Limitations of Management Goals: Potential Consequences of Hypoglycemia Neurogenic symptoms –Tremor, palpitations, anxiety, sweating, hunger (weight gain), paresthesias Neuroglycopenia morbidity –Cognitive impairment, psychomotor abnormalities, abnormal behavior, seizure, coma, mortality (brain death) Rebound hyperglycemia, brittle diabetes Barrier to glycemic control and adherence to treatment secondary to fear of hypoglycemia Greater risk of dementia Prolonged QT interval with increased risk of dysrhythmias, sudden death Harm to property or to others (eg, if driving) 4 Cryer PE. J Clin Invest. 2007;117:868-870. Cryer PE. Diabetes Care. 2003;26:1902-1912.

5. Mortality Risk Mortality Benefit Glucose Control and Mortality: ACCORD Posthoc Analysis 66%<0.0001 Risk increase with each 1% increase in A1C P Value 14%0.17 1 0 6789 Adjusted Log (Hazard Ratio) by Treatment Strategy Relative to Standard at A1C of 6% Log (Hazard Ratio) Average A1C (%) Standard Intensive Riddle MC, et al. Diabetes Care. 2010;33:983-990. 5

6. Algorithm for Individualizing Glycemic Targets 6 Ismail-Beigi F, Moghissi E, et al. Ann Intern Med. 2011;154:554-559. Highly motivated, adherent, knowledgeable, excellent self-care capacities, and comprehensive support systems Less motivated, nonadherent, limited insight, poor self-care capacities, and weak support systems Psychosocioeconomic considerations Hypoglycemia risk LowModerateHigh Patient age, years 4045505560657075 Disease duration, years 5101520 Other comorbid conditions NoneFew or mildMultiple or severe Established vascular complications NoneCardiovascular disease Early microvascularAdvanced microvascular Most intensiveLess intensiveLeast intensive 6.0%7.0%8.0%

7. ADA-Recommended Approach to Management of Hyperglycemia Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379. More StringentLess Stringent Patient attitude and expected treatment efforts Highly motivated, adherent, excellent self-care capacities Less motivated, nonadherent, poor self-care capacities Risks potentially associated with hypoglycemia, other adverse events LowHigh Disease duration Newly diagnosedLong-standing Life expectancy LongShort Resources, support system Readily availableLimited Important comorbidities AbsentSevereFew/mild Established vascular complications AbsentSevereFew/mild 7

8. Hyperglycemia and Microvascular Complications 8

9. Hyperglycemia-Induced Tissue Damage: General Features 9 Diabetic tissue damage Genetic determinants of individual susceptibility Repeated acute changes in cellular metabolism Cumulative long-term changes in stable macromolecules Independent accelerating factors (eg, hypertension, dyslipidemia) Hyperglycemia Brownlee M. Diabetes. 2005;54:1615-1625.

10. Microvascular Complications of Diabetes 10 NephropathyRetinopathyNeuropathy

11. Microvascular Complications Increase With Increasing A1C 0 2 4 6 8 10 12 14 16 18 20 6789101112 Relative Risk Retinopathy Nephropathy Neuropathy Microalbuminuria A1C (%) Diabetes Control and Complications Trial Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254. 11

12. Reducing A1C Reduces Microvascular Risk United Kingdom Prospective Diabetes Study Stratton IM, et al. BMJ. 2000;321:405-412. 12 37% Decrease per 1% reduction in A1C Updated Mean A1C Microvascular Complications Hazard Ratio 0.5 1 10 056789 P<0.0001

13. Reducing A1C Reduces Nephropathy Risk in T2DM 13 UKPDSADVANCEACCORD A1C reduction (%)*0.90.81.3 Nephropathy risk reduction (%)* 3021 New onset micro- albuminuria (P=0.033) New or worsening nephropathy (P=0.006) New microalbuminuria (P=0.0005) *Intensive vs standard glucose control. 1. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853. 2. ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572. 3. Ismail-Beigi F, et al. Lancet. 2010;376:419-430.

14. Prevalence of CKD in Diagnosed Diabetes *Pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies. ESRD, end-stage renal disease; GFR, glomerular filtration rate (mL/min/1.73 m 2 ); NKF, National Kidney Foundation. CDC. National diabetes fact sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Plantinga LC, et al. Clin J Am Soc Nephrol. 2010;5:673-682. NKF Stage DescriptionGFR 1 Kidney damage* with normal or  GFR ≥90 2 Kidney damage* with mild  GFR 60-89 3 Moderate  GFR 30-59 4 Severe  GFR 15-29 5 Kidney failure or ESRD <15 or dialysis Diabetic Kidney Disease Is the Leading Cause of Kidney Failure in the United States 14

15. Genetically susceptible individuals Hyperglycemia Hypertension  Angiotensin II Hyperglycemia Hypertension  Angiotensin II Hyperfiltration Enlarged kidneys Hyperfiltration Enlarged kidneys Breakdown of glomerular filtration barrier Micro- albuminuria Macro- albuminuria Decreasing GFR Capillary occlusion Protein reabsorption and accumulation in renal epithelial cells Release of vasoactive and inflammatory cytokines Tubule and podocyte damage Tubular atrophy and fibrosis, podocyte destruction Development of Diabetic Nephropathy 15 Radbill B, et al. Mayo Clin Proc. 2008;83:1373-1381. Remuzzi G, Bertani T. N Engl J Med. 1998;339:1448-1456. Renal failure

16. CV Risk Increases With Comorbid Diabetes and CKD AMI, acute myocardial infarction; ASVD, atherosclerotic vascular disease; CHF, congestive heart failure; CVA/TIA, cerebrovascular accident/transient ischemic attack; PVD, peripheral vascular disease. *ASVD was defined as the first occurrence of AMI, CVA/TIA, or PVD. Foley RN, et al. J Am Soc Nephrol. 2005;16:489-495. x 2.8 x 2.3 x 1.7 x 2.1 x 2.0 x 2.5 16

17. Appropriate Staging and Management of DKD DKD, diabetic kidney disease. *Includes actions from preceding stages. † Pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies. National Kidney Foundation. Am J Kidney Dis. 2002;39(suppl 1):S1-S266. StageDescription GFR (mL/min/1.73 m 2 ) Action* 1 Kidney damage † with normal or  GFR ≥90 Diagnose and treat CKD, slow progression of CKD, treat comorbid conditions, reduce CVD risk factors 2 Kidney damage † with mild  GFR 60-89Estimate progression 3 Moderate  GFR 30-59Evaluate and treat complications 4 Severe  GFR 15-29 Prepare for kidney replacement therapy 5 Kidney failure <15 or dialysis Kidney replacement, if uremia present ESRDRenal replacement therapy 17

18. KDIGO CKD Classification by Relative Risk 18 Albuminuria stages (mg/g) A1A2A3 Optimal and high normal High Very high and nephrotic <1010-2930-299300-1999≥2000 GFR stages (mL/min per 1.73 m 2 body surface area) G1 High and optimal >105 Very low LowModerateVery high 90-104 G2Mild 75-89 Very low LowModerateVery high 60-74 G3a Mild to moderate 45-59Low ModerateHighVery high G3b Moderate to severe 30-44Moderate High Very high G4Severe15-29High Very high G5 Kidney failure <15Very high Levey AS, et al. Kidney Int. 2011;80:17-28.

19. DKD Risk Factor Management Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S179. Risk FactorGoalManagement Recommendation Hyperglycemia Individualized A1C goals ≤6.5% for most (AACE) <7.0% (NKF) Avoid biguanide in moderate to severe CKD Consider need for dose reductions and/or risk of hypoglycemia and other renal-related AEs with other antidiabetic agents HypertensionBP <130/80 mmHg Use ACE inhibitor or ARB in combination with other antihypertensive agents as needed ProteinuriaUse ACE inhibitor or ARB as directed Dyslipidemia LDL-C <100 mg/dL, <70 mg/dL an option for high risk Statin therapy recommended Fibrate dose reduction may be required 19

20. Use of Noninsulin Antidiabetic Therapies in Patients With Kidney Disease Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379. Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S179. ClassAgent(s)Kidney Disease Recommendation Amylin analogPramlintideNo dosage adjustment ThiazolidinedionesPioglitazone, rosiglitazoneNo dosage adjustment Bile acid sequestrantColesevelamNo dosage adjustment DPP-4 inhibitorsLinagliptin, saxagliptin, sitagliptin Reduce dosage for saxagliptin and sitagliptin if CrCl <50 mg/dL Dopamine-2 agonistBromocriptineUse with caution GlinidesNateglinide, repaglinide Use lowest effective dose of nateglinide for stage ≥3 CKD Insulin Aspart, detemir, glargine, glulisine, lispro, NPH, regular Dosage reduction needed in stage 4-5 CKD SulfonylureasGlimepiride, glipizide, glyburide Glimepiride preferred, use lowest effective dose; avoid other SUs GLP-1 receptor agonistsExenatide, exenatide XR, liraglutide Use with caution in stage 3 CKD; avoid in stage 4-5 CKD  -Glucosidase inhibitors Acarbose, miglitol Not recommended if SCr >2 mg/dL; avoid in dialysis BiguanideMetformin Contraindicated if SCr >1.5 in men or 1.4 in women 20

21. Dietary Guidelines for DKD CKD Stage Macronutrient1-21-43-4 Sodium<2.3 Total fat, % calories*<30 Saturated fat, % calories<10 Cholesterol, mg/day<200 Carbohydrate, % calories50-60 Protein, g/kg/day (% calories)0.8 (~10)0.6-0.8 (~8-10) Phosphorus1.70.8-1.0 Potassium>42.4 *Adjust so total calories from protein, fat, and carbohydrate are 100%. Emphasize such whole-food sources as fresh vegetables, whole grains, nuts, legumes, low-fat or nonfat dairy products, canola oil, olive oil, cold-water fish, and poultry. Tailor dietary counseling to cultural food preferences. Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S179. 21

22. Reducing A1C Reduces Retinopathy Progression in T2DM 22 *Intensive vs standard glucose control. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853. Ismail-Beigi F, et al. Lancet. 2010;376:419-430. Chew EY, et al. N Engl J Med. 2010;363:233-244. UKPDSACCORD A1C reduction (%)0.91.3 Retinopathy risk reduction (%)* 291733 Retinopathy onset (P=0.003) Retinopathy progression (P=0.017) Retinopathy progression (P=0.003)

23. Prevalence of Diabetic Retinopathy *Severe NPDR, PDR, or clinically significant macular edema. NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy; T2DM, type 2 diabetes mellitus. CDC. National diabetes fact sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Zhang X, et al. JAMA. 2010;304:649-656. NHANES 2005-2008 Adults Age ≥40 Years (N=1006) Diabetic Retinopathy Is the Leading Cause of Adult Blindness in the United States 23

24. Diabetic Retinopathy Management Lesion TypeManagement Recommendation Background or nonproliferative retinopathy Optimal glucose and blood pressure control Macular edemaOptimal glucose and blood pressure control Ranibizumab injection therapy Focused laser photocoagulation guided by fluorescein angiography Preproliferative retinopathyOptimal glucose and blood pressure control Panretinal scatter laser photocoagulation Proliferative retinopathyOptimal glucose and blood pressure control Panretinal scatter laser photocoagulation Vitrectomy for patients with persistent vitreous hemorrhage or significant vitreous scarring and debris Goal: detect clinically significant retinopathy before vision is threatened Annual dilated eye examination by experienced ophthalmologist, starting at diagnosis for all T2DM patients Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. 24

25. Reducing A1C Reduces Neuropathy Risk in T2DM 25 *Intensive vs standard glucose control. Ismail-Beigi F, et al. Lancet. 2010;376:419-430. ACCORD A1C reduction (%)1.3 Neuropathy risk reduction (%)* 12 Loss of sensation to light touch (P=0.045)

26. Neuropathy is a heterogenous disorder 70% to 100% of T2DM patients may have at least mild damage to –Proximal nerves –Distal nerves –Somatic nerves –Autonomic nerves Neuropathy may be –Acute and self-limiting –Chronic and indolent Prevalence of Diabetic Neuropathy 26 CDC. National diabetes fact sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Gregg EW, et al. Diabetes Res Clin Pract. 2007;77:485-488. Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. NHANES 1999-2004 Adults With Diabetes, Age ≥40 Years 3 (N=559) Diabetic Peripheral Neuropathy Is the Leading Cause of Nontraumatic Amputations in the United States

27. Diabetic Neuropathies: Key Characteristics and Management Recommendations TypeCondition(s)Clinical FeaturesTreatment FocalMononeuritisSingle nerve involvement Entrapment  Carpal tunnel syndrome  Proximal lumbosacral  Thoracic  Cervical radiculoplexus neuropathies involving the proximal limb girdle Inflammatory demyelinating conditions Immunotherapy 27 Optimize glucose, lipid, and blood pressure control for all T2DM patients Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

28. Diabetic Neuropathies: Key Characteristics and Management Recommendations TypeCondition(s)Clinical FeaturesTreatment Distal neuropathy Large-fiber sensorimotor polyneuropathy Symmetric, glove and stocking distribution with  Loss of sensation  Poor coordination  Ataxia Low-impact activities that improve muscular strength and coordination and challenge the vestibular system  Pilates  Yoga  Tai Chi Small-fiber neuropathy Symmetric, glove and stocking distribution with  Loss of sensation  Pain  Autonomic features Protect insensate feet from ulceration  Padded socks  Daily inspection by patient  Moisturizing lotions Treat neuropathic pain  Amitriptyline  Gabapentin  Pregabalin  Duloxetine  Topical lidocaine 28 Optimize glucose, lipid, and blood pressure control for all T2DM patients Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

29. Diabetic Neuropathies: Key Characteristics and Management Recommendations TypeCondition(s)Clinical FeaturesTreatment AutonomicCardiacSymptoms  Tachycardia  Exercise intolerance  Orthostatic hypotension, weakness, fatigue, syncope Associated with significant mortality and possibly also  Silent myocardial ischemia  Coronary artery disease  Stroke  Diabetic nephropathy progression  Perioperative morbidity Intensive control of CV risk factors For tachycardia, exercise intolerance  Supervised exercise  ACE inhibitors  -adrenergic blockers For hypotension, weakness, etc  Mechanical measures  Clonidine  Midodrine  Octreotide  Erythropoietin 29 Optimize glucose, lipid, and blood pressure control for all T2DM patients Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

30. Diabetic Neuropathies: Key Characteristics and Management Recommendations TypeCondition(s)Clinical FeaturesTreatment AutonomicGastrointestinalGastroparesis, erratic glucose controlFrequent small meals Prokinetic agents  Metoclopramide  Domperidone  Erythromycin Abdominal pain, early satiety, nausea, vomiting, bloating, belching Antibiotics Antiemetics Bulking agents Tricyclic antidepressants Pyloric Botox Gastric pacing ConstipationHigh-fiber diet Bulking agents Osmotic laxatives Lubricating agents Diarrhea (often nocturnal, alternating with constipation) Soluble dietary fiber Gluten and lactose restriction Anticholinergic agents Cholestyramine Antibiotics Somatostatin Pancreatic enzyme supplements 30 Optimize glucose, lipid, and blood pressure control for all T2DM patients Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

31. Diabetic Neuropathies: Key Characteristics and Management Recommendations TypeCondition(s)Clinical FeaturesTreatment AutonomicSexual dysfunctionErectile dysfunctionSex therapy Psychological counseling 5′-phosphodiesterase inhibitors Prostaglandin E1 injections Devices Prostheses Vaginal drynessVaginal lubricants Bladder dysfunctionFrequency, urgency, nocturia, urinary retention, incontinence Bethanechol Intermittent catheterization Sudomotor dysfunction Anhidrosis Heat intolerance Dry skin Hyperhidrosis Emollients and skin lubricants Scopolamine Glycopyrrolate Botulinum toxin Vasodilators 31 Optimize glucose, lipid, and blood pressure control for all T2DM patients Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

32. Hyperglycemia and Macrovascular Complications 32

33. Diabetes Is a Cardiovascular Disease Risk Equivalent 7-Year Incidence of MI (%) Diabetic (n=1059) Prior MINo prior MIPrior MINo prior MI Nondiabetic (n=1373) MI, myocardial infarction. Grundy SM, et al. Circulation. 2004;110:227-239. Haffner SM, et al. N Engl J Med. 1998;339:229-234. 33 P<0.001

34. Lower A1C Is Associated With Lower Risk of Myocardial Infarction Stratton IM et al. BMJ. 2000;321:405-412. United Kingdom Prospective Diabetes Study 14% Decrease per 1% reduction in A1C Updated Mean A1C 0.5 1 10 056789 P<0.0001 Myocardial Infarction Hazard Ratio 34

35. 0.12 0.10 0.08 0.06 0.02 Randomized treatment Randomized treatment Intensive Glycemic Control Reduces Long-term Macrovascular Risk in Younger Patients With Shorter Duration of Disease 35 Randomized treatment Randomized treatment 0.04 0.00 05101520 No. at Risk Conventional71468861892 Intensive705683629113 Years DCCT T1DM, 5-6 years duration (N=1441) 42% risk reduction P=0.02 Conventional Intensive CV Outcome Cumulative incidence UKPDS T2DM, newly diagnosed (N=4209) 15% risk reduction P=0.01 1138101385757822120 272924882097145957766 1.0 0.8 0.6 0.4 0.2 0.0 05102025 Years Conventional Intensive Proportion With MI 15 CV, cardiovascular; DCCT, Diabetes Control and Complications Trial; MI, myocardial infarction; UKPDS, United Kingdom Prospective Diabetes Study. Nathan DM, et al. N Engl J Med. 2005;353:2643-2653. Holman RR, et al. N Engl J Med. 2008;359:1577-1589.

36. ACCORDADVANCEVADT T2DM duration (years)10812 A1C reduction (%)*0.90.81.3 Macrovascular risk (%)* 10612 P=0.16 Mortality increased in intensively treated patients (P=0.04) P=0.32P=0.14 Intensive Glycemic Control Does Not Reduce Macrovascular Risk in Older Patients With Longer Duration of Disease 36 *Intensive vs standard glucose control. ACCORD Study Group. N Engl J Med. 2008;358:2545-2559. ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572. Duckworth W, et al. N Engl J Med. 2009;360:129-139.

37. Macrovascular Risk Reduction in T2DM Individualized glucose control Hypertension control Dyslipidemia control Smoking cessation Aspirin therapy Diagnosis and management of: –Autonomic cardiac neuropathy –Kidney disease 37 Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.