Type 2 Diabetes Management Goals

Type 2 Diabetes Management Goals

Glucose Goals and Complications Management for Type 2 Diabetes 1 Type 2 Diabetes Glucose Goals and Complications Management INDIVIDUALIZED GOALS 2 AACE Comprehensive Diabetes Care: Glucose Goals Parameter Treatment Goal for Nonpregnant Adults A1C (%) Individualize targets: 6.5 if it can be achieved without substantial hypoglycemia or other unacceptable consequences >6.5% to 8% for those at risk* FPG (mg/dL) <110 2- hour PPG (mg/dL) <140 *As long as patient remains free of polydipsia, polyuria, polyphagia, or other symptoms of hyperglycemia. Factors indicating a higher A1C target include

Risk for hypoglycemia History of severe hypoglycemia Limited life expectancy Long-standing T2D in which the A1C goal has been difficult to attain despite intensive efforts Handelsman Y, et al. Endocr Pract. 2015;21(suppl 1):1-87. Garber AJ, et al. Endocr Pract. 2018;24:91-120. 3 Algorithm for Individualizing Glycemic Targets Most intensive 6.0% Less intensive 7.0% Least intensive 8.0% Psychosocioeconomic considerations Less motivated, nonadherent, limited insight, poor self-care capacities, and weak support systems Highly motivated, adherent, knowledgeable, excellent self-care capacities, and comprehensive support systems Hypoglycemia risk Moderate High Low 40

45 50 5 None None Ismail-Beigi F, Moghissi E, et al. Ann Intern Med. 2011;154:554-559. 55 60 10 Few or mild 65 Patient age, years 70 75 15 Disease duration, years 20 Other comorbid conditions Multiple or severe Established vascular complications Cardiovascular disease Early microvascular Advanced microvascular 4 ADA-Recommended Glucose Goals Parameter

Treatment Goal for Nonpregnant Adults A1C (%) Individualize <7.0% for most nonpregnant adults <6.5 if it can be achieved without significant hypoglycemia or other adverse effects of treatment* <8% for those at risk Preprandial glucose (mg/dL) 80-130 Peak postprandial glucose (mg/dL) <180 *Appropriate patients Short duration of diabetes T2D treated only with lifestyle or metformin Long life expectancy No significant cardiovascular disease ADA. Diabetes Care. 2018;41:S55-S64. At risk patients History of severe hypoglycemia Limited life expectancy Advanced micro- or macrovascular complications Extensive comorbid conditions Long-standing T2D in which A1C goal has been difficult to attain despite intensive efforts 5

ADA-Recommended Approach to Management of Hyperglycemia More stringent A1C 7% Less stringent Risks potentially associated with hypoglycemia, other Low drug adverse events High Disease duration Newly diagnosed Life expectancy Important comorbidities Long-standing Long Short Absent Few/mild Severe Established vascular complications Absent Few/mild Severe Patient attitude and Highly motivated, adherent, expected treatment efforts excellent self-care capacities Resources, support system

ADA. Diabetes Care. 2018;41:S55-S64. Readily available Less motivated, nonadherent, poor self-care capacities Usually not modifiable Potentially modifiable Limited 6 Risk Factors for Hypoglycemia Well- Known Risks Use of insulin secretagogues or 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 Amiel SA, et al. Diabet Med. 2008;25:245-254. ADA. Diabetes Care. 2005;28:1245-1249.

Less Well-Known Risks Female sex African-American race Lower education level 7 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) Cryer PE. J Clin Invest. 2007;117:868-870. Cryer PE. Diabetes Care. 2003;26:1902-1912. 8 Hypoglycemia and Mortality ACCORD Posthoc Analysis Risk of Hypoglycemia with Each 1% Change in Updated A1C Risk of Mortality in Patients with Severe Hypoglycemia 2.9X 76%

Standard Intensive 15% 14% 28% 28% 1% Decrease Miller ME, et al. BMJ. 2010;340:b5444-b5444. 1% Increase 9 Glucose Control and Mortality ACCORD Posthoc Analysis Adjusted Log (Hazard Ratio) by Treatment Strategy Relative to Standard at A1C of 6% Log (Hazard Ratio) Mortality Risk Intensive Risk increase with each 1% increase in A1C P Value 1 66% <0.0001 0 14% Standard -1

0.17 Mortality Benefit 6 7 8 9 Average A1C (%) Riddle MC, et al. Diabetes Care. 2010;33:983-990. 10 A1C and Mortality in Clinical Practice All-cause mortality hazard ratio Retrospective Cohort Study (N=27,965) A1C (%) Currie CJ, et al. Lancet. 2010;375:481-489. 11 Macrovascular Benefits of Glycemic Control Depend on Duration of Diabetes Veterans Affairs Diabetes Trial Effect of intensive glycemic control 4.0 Neutral 3.5

Reduced risk Neutral Elevated risk Hazard ratio 3.0 2.5 2.0 1.5 1.0 0.5 0 0 3 6 9 12 15 18 21 24 27 30 Years with diabetes VADT, Veterans Affairs Diabetes Trial. Duckworth WC, et al. J Diabetes Complications. 2011;25:355-361. 12 Type 2 Diabetes Glucose Goals and Complications Management MICROVASCULAR COMPLICATIONS

13 Hyperglycemia-Induced Tissue Damage: General Features Genetic determinants of individual susceptibility Repeated acute changes in cellular metabolism Hyperglycemia Cumulative long-term changes in stable macromolecules Diabetic tissue damage Independent accelerating factors (eg, hypertension, dyslipidemia) Brownlee M. Diabetes. 2005;54:1615-1625. 14 Microvascular Complications of Diabetes Nephropathy Retinopathy Neuropathy 15 Microvascular Complications Increase With Increasing A1C Diabetes Control and Complications Trial 20

Retinopathy 18 Nephropathy Relative Risk 16 Neuropathy 14 Microalbuminuria 12 10 8 6 4 2 0 6 7 Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254. 8 9 A1C (%) 10 11 12

16 Reducing A1C Reduces Microvascular Risk United Kingdom Prospective Diabetes Study Microvascular Complications Hazard Ratio 10 P<0.0001 1 37% Decrease per 1% reduction in A1C 0.5 0 5 6 7 8 9 10 Updated Mean A1C Stratton IM, et al. BMJ. 2000;321:405-412. 17 Prevalence of CKD in Diagnosed Diabetes

Diabetic Kidney Disease Is the Leading Cause of Kidney Failure in the United States Stage 1; 0.1% NKF Stage Stage 2; 0.13% kidney disease; 0.61% Description GFR 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 Stage 3; 0.14% Stage 4; 0.01% *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 m2); 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. 18 Development of Diabetic Nephropathy Hyperglycemia Hypertension Angiotensin II Hyperfiltration Enlarged kidneys Breakdown of glomerular filtration barrier Microalbuminuria Genetically susceptible individuals Protein reabsorption and accumulation in renal epithelial cells Capillary occlusion Decreasing

GFR Macroalbuminuria Release of vasoactive and inflammatory cytokines Tubule and podocyte damage Tubular atrophy and fibrosis, podocyte destruction Renal failure Radbill B, et al. Mayo Clin Proc. 2008;83:1373-1381. Remuzzi G, Bertani T. N Engl J Med. 1998;339:1448-1456. 19 In c i d e n c e p e r 1 0 0 P a ti e n t - Y e a r s CV Risk Increases With Comorbid Diabetes and CKD x 2.8 x 2.0 No diabetes/no CKD Diabetes/no CKD Diabetes/CKD 60

50 x 1.7 40 x 2.1 x 2.5 30 20 x 2.3 10 0 CHF AMI CVA/TIA PVD ASVD* Death 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. 20 Risk of Cardiovascular Mortality with Decreasing eGFR and Increasing Albuminuria 14 12

ath e D lar u c s va o i d Car f o Risk Relative Risk 10 8 6 4 2 0 >105 90-105 75-90 60-75 45-60 eGFR (mL/min/1.73 m2) 30-45 15-30

300 ACR (mg/g) 30-299 10-29 <10 ACR = albumin-creatinine ratio; eGFR = estimated glomerular filtration rate. Handelsman Y, et al. Endocr Pract. 2015;21(suppl 1):1-87. NKF. Kidney Int Suppl. 2013;3:1-150. 21 KDIGO CKD Classification by Relative Risk Albuminuria stages (mg/g) GFR stages (mL/min per 1.73 m2 body surface area) >105 A1 A2 A3 Optimal and high normal High Very high and nephrotic <10 10-29

30-299 300-1999 2000 Very low Very low Low Moderate Very high Very low Very low Low Moderate Very high G1 High and optimal G2 Mild G3a Mild to moderate

45-59 Low Low Moderate High Very high G3b Moderate to severe 30-44 Moderate Moderate High High Very high G4 Severe 15-29 High High High

High Very high G5 Kidney failure <15 Very high Very high Very high Very high Very high Levey AS, et al. Kidney Int. 2011;80:17-28. 90-104 75-89 60-74 22 Staging and Monitoring of CKD in Diabetes Persistent albuminuria categories Description and range GFR categories (mL/min/1.73 m )2 Description and range Previous NKF CKD

stage Guide to frequency of monitoring (number of times per year) by GFR and albuminuria category A1 A2 A3 Normal to mildly increased Moderately increased Severely increased <30 mg/g <3 mg/mmol 30-300 mg/g 3-30 mg/mmol >300 mg/g >30 mg/mmol 1 G1 Normal or high 90 1 if CKD 1

2 2 G2 Mildly decreased 60-89 1 if CKD 1 2 G3a Mild to moderately decreased 45-59 1 2 3 G3b Moderately to severely decreased 30-44 2 3

3 4 G4 Severely decreased 15-29 3 3 4+ 5 G5 Kidney failure <15 4+ 4+ 4+ 3 CKD = chronic kidney disease; GFR = glomerular filtration rate; NKF = National Kidney Foundation. Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 23 Reducing A1C Reduces Nephropathy Risk in T2D

UKPDS ADVANCE ACCORD A1C reduction (%)* 0.9 0.8 1.3 Nephropathy risk reduction (%)* 30 21 21 New onset microalbuminuria (P=0.033) New or worsening nephropathy (P=0.006) New microalbuminuria (P=0.0005) *Intensive vs standard glucose control. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853. ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572.

Ismail-Beigi F, et al. Lancet. 2010;376:419-430. 24 Management of Diabetic Nephropathy Optimal control of blood pressure, glucose, and lipids Smoking cessation RAAS blockade ACE inhibitor, ARB, or renin inhibitor Do not combine RAAS blocking agents Monitor serum potassium Nephrologist referral Atypical presentation Rapid decline in eGFR or albuminuria progression Stage 4 CKD ACE = angiotensin converting enzyme; ARB = angiotensin II receptor blocker; CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; RAAS = renin angiotensin aldosterone system. Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 25 DKD Risk Factor Management Risk Factor Goal Management Recommendation Hyperglycemia Individualized A1C goals 6.5% for most (AACE) ~7.0% (NKF) Avoid metformin in moderate to severe CKD Consider need for dose reductions and/or risk of hypoglycemia and other renal-related AEs with other antidiabetic agents

Do not target A1C <7% in patients at risk of hypoglycemia Hypertension BP ~130/80 mmHg Use ACE inhibitor or ARB in combination with other antihypertensive agents as needed Proteinuria Dyslipidemia Use ACE inhibitor or ARB as directed LDL-C <100 mg/dL, <70 mg/dL an option for high risk Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S179. National Kidney Foundation. Am J Kidney Dis. 2012;60:850-886. Statin +/- ezetimibe therapy recommended for all patients except those on dialysis (NKF) Fibrate dose reduction may be required 26 Use of Antihyperglycemic Agents in Kidney Disease Class: Agent(s) Kidney Disease Recommendation Amylin analog: pramlintide Not recommended for CKD stage 4 Biguanide: metformin

Contraindicated if SCr >1.5 (men) or 1.4 (women) mg/dL Bile acid sequestrant: colesevelam No dosage adjustment Dopamine-2 agonist: bromocriptine Use with caution DPP-4 inhibitors: alogliptin, linagliptin, saxagliptin, sitagliptin Reduce dosage for alogliptin, saxagliptin and sitagliptin if CrCl <50 mg/dL Glinides: nateglinide, repaglinide Start at lowest effective dose if GFR <30 mL/min/1.73 m 2 GLP-1 receptor agonists: albiglutide, dulaglutide, exenatide, exenatide XR, liraglutide Exenatide and liraglutide not recommended with GFR <30 mL/min/ -Glucosidase inhibitors: acarbose, miglitol Avoid if GFR <25 (miglitol) or <30 (acarbose) mL/min/1.73 m2 Insulin: aspart, detemir, glargine, glulisine, inhaled, lispro, NPH, Adjust dose based on patient response regular SGLT inhibitors: canagliflozin, dapagliflozin, empagliflozin Ineffective if GFR <30 mL/min/1.73 m2 Sulfonylureas: glimepiride, glipizide, glyburide No dose adjustment for glipizide; start glimepiride conservatively; avoid glyburide and all other SUs

Thiazolidinediones: pioglitazone, rosiglitazone No dosage adjustment Garber AJ, et al. Endocr Pract. 2017;23:207-238. ADA. Diabetes Care. 2017;40:S64-S74. Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. National Kidney Foundation. Am J Kidney Dis. 2012;60:850-886. 27 Dietary Guidelines for DKD CKD Stage 1-4 <2.3 <30 <10 <200 50-60 Macronutrient 1-2 3-4 Sodium Total fat, % calories* Saturated fat, % calories Cholesterol, mg/day Carbohydrate, % calories Protein, g/kg/day (% calories) 0.8 (~10) 0.6-0.8 (~8-10) Phosphorus 1.7 0.8-1.0 Potassium >4 2.4 *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.

National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S179. 28 Diabetic Retinopathy NHANES 2005-2008 Adults Age 40 Years (N=1006) None; 71.5% All T2D patients should have a dilated eye examination by experienced ophthalmologist annually, starting at diagnosis to detect clinically significant retinopathy before vision is threatened Vision-threatening*; 4.4% Lesion types NPDR; 24.1% Background or nonproliferative retinopathy Macular edema Preproliferative retinopathy

Proliferative retinopathy *Severe NPDR, PDR, or clinically significant macular edema. NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy; T2D, type 2 diabetes. Zhang X, et al. JAMA. 2010;304:649-656. Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 29 Reducing A1C Reduces Retinopathy Progression in T2D A1C reduction (%) Retinopathy risk reduction (%)* UKPDS ACCORD 0.9 1.3 29 17 33 Retinopathy onset (P=0.003) Retinopathy progression (P=0.017) Retinopathy

progression (P=0.003) *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. 30 Assessment of Diabetic Retinopathy Annual dilated eye examination by experienced ophthalmologist or optometrist Begin assessment 5 years after diagnosis of T1D At diagnosis of T2D More frequent examinations for: Pregnant women with DM during pregnancy and 1 year postpartum Patients with diagnosed retinopathy Patients with macular edema receiving active therapy Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 31 Diabetic Retinopathy Management Goal: detect clinically significant retinopathy before vision is threatened Annual dilated eye examination by experienced ophthalmologist, starting at diagnosis for all T2D patients Lesion Type Background or nonproliferative retinopathy Macular edema Management Recommendation Optimal glucose and blood pressure control Preproliferative retinopathy

Proliferative retinopathy Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. Optimal glucose and blood pressure control Ranibizumab injection therapy Focused laser photocoagulation guided by fluorescein angiography Optimal glucose and blood pressure control Panretinal scatter laser photocoagulation Optimal glucose and blood pressure control Panretinal scatter laser photocoagulation Vitrectomy for patients with persistent vitreous hemorrhage or significant vitreous scarring and debris 32 Prevalence of Diabetic Neuropathy NHANES 1999-2004 Adults With Diabetes, Age 40 Years (N=559) DPN; 18.5% Neuropathy is a heterogeneous disorder 70% to 100% of T2D patients may have at least mild damage to

Proximal nerves Distal nerves Somatic nerves Autonomic nerves Neuropathy may be None; 81.5% Acute and self-limiting Chronic and indolent T2D, type 2 diabetes. Gregg EW, et al. Diabetes Res Clin Pract. 2007;77:485-488. Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. 33 Causes of Death in Diabetic Autonomic Neuropathy Sudden unexplained Cardiac arrhythmia Silent myocardial infarction More likely to die of heart attack Greater incidence of cardiac failure Aspiration pneumonia Ulcers, amputations, gangrene Chronic renal failure Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 34 Relative Risk of Mortality from Cardiac Autonomic Neuropathy Prevalence Rate Ratios and 95% CI from 15 Studies (P<0.0001; N=2900)

Study 1 Study 2 Study 3 Study 4 Study 5 Study 6 Study 7 Study 8 Study 9 Study 10 Study 11 Study 12 Study 13 Study 14 Study 15 2.14 (1.83-2.51); 3.45 if >2 abnormalities Pooled Data 0 Vinik AI, et al. Diabetes Care. 2003;26:1553-1579. Maser RE, et al. Diabetes Care. 2003;26:1895-1901. 1 10 100 Log Relative Risk 35 Reducing A1C Reduces Neuropathy Risk in T2D ACCORD A1C reduction (%) 1.3

Neuropathy risk reduction (%)* 12 Loss of sensation to light touch (P=0.045) *Intensive vs standard glucose control. Ismail-Beigi F, et al. Lancet. 2010;376:419-430. 36 Assessment of Diabetic Neuropathy Complete neurologic examination annually Begin assessment 5 years after diagnosis of T1D At diagnosis of T2D Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 37 Diabetic Neuropathy Evaluations and Tests Foot inspection Neurologic testing Painful neuropathy Cardiovascular autonomic neuropathy Foot structure and deformities Skin temperature and integrity Ulcers Vascular status Pedal pulses Amputations Loss of sensation, using 1 and 10-g monofilament

Vibration perception using 128-Hz tuning fork Ankle reflexes Touch, pinprick, and warm and cold sensation May have no physical signs Diagnosis may require skin biopsy or other surrogate measure Heart rate variability with: Deep inspiration Valsalva maneuver Change in position from prone to standing Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 38 Diabetic Neuropathy Management All neuropathies Painful neuropathy Large-fiber neuropathies Small-fiber

neuropathies Prevent by controlling blood glucose to individual targets No therapies proven to reverse neuropathy once it is established May slow progression by maintaining optimal glucose, blood pressure, and lipid control and using other interventions that reduce oxidative stress Tricyclic antidepressants, anticonvulsants, serotonin reuptake inhibitors, or norepinephrine reuptake inhibitors Strength, gait, and balance training Orthotics to prevent/treat foot deformities Tendon lengthening for pes equinus Surgical reconstruction Casting Foot protection (eg, padded socks) Supportive shoes with orthotics if needed Regular foot inspection Prevention of heat injury Emollient creams Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 39 Type 2 Diabetes Glucose Goals and Complications Management MACROVASCULAR COMPLICATIONS 40 Macrovascular Complications Cardiovascular disease Coronary artery disease Myocardial infarction Cerebrovascular disease (stroke) Peripheral vascular disease 41

7-Year Incidence of MI (%) Diabetes and Cardiovascular Risk P<0.001 50 45 40 30 P<0.001 20 10 18.8 20.2 Prior MI No prior MI 3.5 0 No prior MI Patients without diabetes (n=1373) Prior MI Patients with diabetes (n=1059)

MI, myocardial infarction. Haffner SM, et al. N Engl J Med. 1998;339:229-234. 42 Lower A1C Is Associated With Lower Risk of Myocardial Infarction United Kingdom Prospective Diabetes Study 10 Myocardial Infarction Hazard Ratio P<0.0001 1 14% Decrease per 1% reduction in A1C 0.5 0 5 Stratton IM et al. BMJ. 2000;321:405-412. 6 7 8 9 Updated Mean A1C 10 43 Effect of Intensive Glycemic Control on Macrovascular Risk in Older Patients With Longer Duration of Disease ACCORD

ADVANCE VADT T2DM duration (years) 10 8 12 A1C reduction (%)* 0.9 0.8 1.3 Macrovascular risk (%)* 10 6 12 P=0.16 (CV death, nonfatal MI, nonfatal stroke) P=0.32 (CV death, nonfatal MI, nonfatal stroke) P=0.14 (CV death, nonfatal MI, nonfatal stroke, CHF, vascular surgery,

inoperable coronary disease, PVD amputation) *Intensive vs standard glucose control. ACCORD, Action to Control Cardiovascular Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation; CHF, congestive heart failure; CV, cardiovascular; MI, myocardial infarction; PVD, peripheral vascular disease; VADT, Veterans Affairs Diabetes Trial. 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. 44 Intensive Glycemic Control May Have Macrovascular Benefit in Healthier People Action to Control Cardiovascular Risk in Diabetes Secondary endpoint (nonfatal MI; entire cohort) Primary endpoint (CV death, nonfatal MI, nonfatal stroke) subgroup analyses Baseline A1C 8% No prior CV events 24 26 21 P=0.004 P=0.03 P=0.04 Risk reduction (%)* *Intensive vs standard glucose control.

CV, cardiovascular; MI, myocardial infarction. ACCORD Study Group. N Engl J Med. 2008;358:2545-2559. 45 Intensive Glycemic Control Reduces Long-term Macrovascular Risk DCCT T1D, 5-6 years duration (N=1441) UKPDS T2D, newly diagnosed (N=4209) 42% risk reduction 0.10 0.08 Conventional Randomized treatment 0.06 0.04 0.02 P=0.01 1.0 Proportion With MI 0.12 CV Outcome Cumulative incidence 15% risk reduction

P=0.02 Intensive 0.00 0.8 0.6 Randomized treatment 0.4 Conventional 0.2 Intensive 0.0 0 5 10 15 20 0 Years 5 10

15 20 25 Years CV, cardiovascular; DCCT, Diabetes Control and Complications Trial; MI, myocardial infarction; T1D, type 1 diabetes; T2D, type 2 diabetes; 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. 46 Long-Term Effect of Intensive Glycemic Control on Macrovascular Risk VADT Follow-up Study Probability of No Event 1.0 0.75 Intensive 17% risk reduction Randomized treatment 0.50 P=0.04 Standard 0.25 0

0 2 4 6 8 10 12 14 Years VADT, Veterans Affairs Diabetes Trial. Hayward RA, et al. N Engl J Med. 2015;372:2197-2206. 47 Effects of Intensive Glucose Control on Macrovascular Risk in T2D Meta-analysis of 5 Prospective RCTs Assessing Effect of Intensive Glucose Lowering on CV Outcomes (ACCORD, ADVANCE, PROactive, UKPDS, VADT) Event Odds ratio Relative risk Nonfatal MI 0.83 (0.75-0.93) -17%

Any CHD event 0.85 (0.77-0.93) -15% Stroke 0.93 (0.81-1.06) -7% (NS) All-cause mortality 1.02 (0.87-1.19) +2% (NS) 0.4 0.6 0.8 Intensive treatment better 1.0 1.2 1.4 1.6 1.8 2.0 Standard treatment better ACCORD, Action to Control Cardiovascular Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation; NS, not significant; PROactive, Prospective Pioglitazone Clinical Trial in Macrovascular Events; T2D, type 2 diabetes; UKPDS, United Kingdom Prospective Diabetes Study; VADT, Veterans Affairs Diabetes Trial.

Ray KK, et al. Lancet. 2009;373:1765-1772. 48 Macrovascular Risk Reduction in Type 2 Diabetes Individualized glucose control Hypertension control Dyslipidemia control Smoking cessation Aspirin therapy Diagnosis and management of: Autonomic cardiac neuropathy Kidney disease Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 49

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