T2DM and Need for Insulin. Insulin Pharmacokinetics. When To Start Insulin in T2DM. FDA-approved Insulins for Subcutaneous Injection

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1 Plasma Insulin Levels Patients Requiring Insulin (%) Effective Use of Insulin in the Primary Care Practice: Insulin Therapy Initiation, Intensification, and the Insulinizing Complex Patients with T2DM: Effectively Using Insulin in the Primary Care Practice Jaime A. Davidson, MD, FACP, MACE Clinical Professor of Medicine Division of Endocrinology University of Texas Southwestern Medical Center Dallas, TX Anne Peters, MD, FACP, CDE Director, Clinical Diabetes Program Professor, Keck School of Medicine University of Southern California Jaime A. Davidson, MD, FACP, MACE Clinical Professor of Medicine Division of Endocrinology University of Texas Southwestern Medical Center Dallas, TX T2DM and Need for Insulin When To Start Insulin in T2DM UKPDS: at 6 years, more than 5% of patients need insulin to reach target (FPG 6. mmol/l) When combination oral/injectable agents become inadequate Unacceptable side effects of other agents Patient with advanced hepatic or renal disease Special circumstances (eg, steroids, infection, pregnancy) Patient with hyperglycemia in the hospital Severely uncontrolled diabetes Wright A, et al. Diabetes Care. 22;25: Years from Randomization Defined as FPG >25 mg/dl, random glucose >3 mg/dl, A1C >1%, ketonuria, or symptomatic (polyuria, polydipsia, and weight loss) by ADA 29 Consensus Statement. After glucose is controlled, oral agents can be added and insulin withdrawn if preferred. Hirsch IB, et al. Clinical Diabetes. 25;23: Nathan DM, et al. Diabetes Care. 29; FDA-approved Insulins for Subcutaneous Injection Insulin Pharmacokinetics Current Insulins Rapid-acting (lispro, aspart, glulisine) Short (regular insulin) Basal Prandial Premixed/ Biphasic Intermediate (NPH insulin) Human insulins (intermediateacting) Analog insulins (long-acting) Human insulins (short-acting) Analog insulins (rapid-acting) Human insulins Analog insulins Long (insulin detemir) Long (insulin glargine) Neutral protamine Hagedorn (NPH) Detemir Regular human insulin (RHI) Aspart Biphasic 7/3 Biphasic 7/3 Glargine U-1 U-5 Glulisine Lispro Premixed 7/3 Premixed 5/5 Premixed 75/25 4: 6: 8: 1: 2: 14: 18: 22: : 12: 16: 2: 24: Time (h) Adapted from: Hirsh IB. N Engl J Med. 25;352: Flood TM. J Fam Pract. 27;56(suppl 1):S1-S12. 1

2 Mean FPG (mg/dl) Mean Plasma Insulin Levels Insulin Effect Number of injections Insulin Therapy in T2DM Complexity Basal insulin 1 only Low Moderate High Basal insulin + 1 mealtime insulin 2,3 injection Basal insulin + 2 mealtime insulin injections Pre-mixed Insulin 4 BID A Recommendation for Starting and Adjusting Basal Insulin Bedtime or morning long-acting insulin OR Bedtime intermediate-acting insulin Daily dose:.1-.2 u/kg Check FBG daily Increase dose by 2 units every 3 days until FPG is 7-13 mg/dl If FPG is >18 mg/l, increase dose by 4 units every 3 days In the event of hypoglycemia or FPG level <7 mg/dl: Reduce bedtime insulin dose by 4 units, or by 1% if >4 units Flexibility More Flexible Less Flexible Continue regimen and check A1C every 3 months 1 Glargine (long-acting analog), Detemir (long-acting analog), or human NPH (intermediate-acting). 2 Human regular (short-acting). 3 Lispro, aspart, or glulisine (rapid-acting analog). 4 7%/3% or 5%/5% NPH/regular, 75%/25% or 5%/5% lispro mix, or 7%/3% aspart mix. FBG = fasting blood glucose. Nathan DM, et al. Diabetes Care. 29;32: Inzucchi SE, et al. Diabetes Care. 212;35(6): Physiologic Insulin Secretion Basal Only Insulin Therapy Breakfast Lunch Dinner Prandial Insulin Endogenous insulin Basal insulin Long (glargine, detemir) 4: 8: Time (hours) Basal Insulin 12: 16: 2: Adapted with permission from: McCall AL. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 22: : 4: BF L D hs BF = breakfast. D = dinner. hs = at bedtime. L = lunch. Adapted with permission: from McCall AL. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 22: Treat-to-Target Trial Hypothetical Barriers to Insulin Use Change of FPG over 24 Weeks Glargine , 12 mg/dl Weeks of Treatment Change of A1C over 24 Weeks NPH % 7% Weeks of Treatment Insulin glargine was associated with 41% risk reduction in hypoglycemia, P<.3 Patient Barriers Fear of injections Fear of hypoglycemia Fear of weight gain Insulin need = severe diabetes Provider Barriers Insulin is atherogenic Concerns over starting, and follow-up of insulin Complexity of use, adjustments Solutions Improved comfort & convenience Severe hypoglycemia rare Weight gain seen with most Rx Glucose lowering is the KEY Solutions NO!! DIGAMI, UKPDS, DCCT Improved devices, insulin use of patient self-management education? Simplify regimens, dosing Riddle MC, et al. Diabetes Care. 23;26:

3 Incidence of Hypoglycemia (%) Patient- vs Physicianadjusted Basal Insulin A1C Change 7.7 Physicianadjusted Patientadjusted 8.9 Baseline 24 Weeks 7.9 Hypoglycemia Patients can be safely instructed to adjust their insulin dose Patient-adjusted Physician-adjusted Severe Symptomatic Nocturnal Premixed (Biphasic) Insulin Analogues Premixed insulins: 75% insulin lispro protamine suspension/25% insulin lispro injection 5% insulin lispro protamine suspension/5% insulin lispro injection 7% insulin aspart protamine suspension/3% insulin aspart injection 7% human insulin isophane suspension/3% human insulin injection 7% NPH, human insulin isophane suspension/3% regular, human insulin injection Premixed insulin may be appropriate: When basal/bolus cannot be used and For those with regular lifestyles who eat similar amounts at similar times each day (similar total calories and similar content for carbohydrate/fat/protein) and Those who wish only 2 injections/day Davies M, et al. Diabetes Care. 25;28: Agency for Healthcare Research and Quality. Available at: Accessed April 14, 214. The INITIATE Trial: A Comparison of Basal Insulin and Biphasic Insulin Analog Therapy The Study: Dosing of Biphasic Insulin N=233 patients with T2DM Continue OAD therapy + glargine 1-12 U Phase 1 1 subjects Daily Pre-dinner 16 wks Start with 12 U at dinner A1C 6.5% 21 completed Phase 1 A1C >8% (insulin-naïve) OAD failures on MET 1 mg/dl Target FPG: 8-11 mg/dl Secretagogues and carbohydrate inhibitors discontinued; rosiglitazone switched to pioglitazone 3 mg/d. OAD = oral antidiabetic. Raskin P, et al. Diabetes Care. 25;28: Continue OAD therapy + biphasic insulin aspart 7/3 5-6 U twice daily 4-week run-in and 28 weeks of treatment with insulin-adjustments titration Phase 2 68 subjects Twice Daily Phase 3 25 subjects Thrice Daily Garber AJ, et al. Diabetes Obes Metab. 26;8: Pre-breakfast & dinner 16 wks Add 3 U at breakfast if FPG 11 Add 6 U at breakfast if FPG >11 Thrice daily 16 wks Add 3 U at lunch Titrate according to schedule every 3 days If A1C > 6.5%, go to twice daily and discontinue secretagogues A1C 6.5% If A1C >6.5%, go to thrice daily 28 completed Phase 2 25 completed Phase 3 The INITIATE Trial: Biphasic Insulin Analog Therapy Resulted in Greater Reductions in A1C than Basal Insulin Analog Therapy When Is Basal Alone Not Enough? P= Biphasic insulin aspart twice daily Insulin glargine once daily P=.1 When A1C values are still not at target AND Basal insulin dose titrated to.4-.6 units/kg/day Fasting BG levels at or approaching target Post-prandial BG values remain above target Baseline 28 Weeks Raskin P, et al. Diabetes Care. 25;28:

4 Insulin Effect How to Intensify Using the Basal Plus Approach Mimicking Physiologic Insulin Secretion: Basal-bolus Insulin Therapy Choose the target meal to initiate prandial coverage: Breakfast or the largest meal of the day Start 4-6 units of a rapid-acting insulin analog: 1-15 minutes before the meal Adjust prandial insulin dose based on: 2-h PPG target <18 mg/dl Next pre-prandial or HS BG target <13 mg/dl If A1C remains above target add 2 nd prandial dose: Usually need about 8-12 units of prandial insulin to cover meal(s) Rapid (lispro, aspart, glulisine) BF L D hs Endogenous insulin Basal insulin Bolus insulin Long (glargine, detemir) PPG = postprandial glucose. Lankisch MR, et al. Diabet Obes and Metab. 28:1; Meneghini L, et al. Endocr Pract. 211;17; Adapted with permission from McCall AL. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 22: Requirements of Multi-dose Insulin Therapy Requires understanding of insulin action: Basal-bolus therapy generally 5% basal/5% bolus Critical role of patient education: Nutrition education Carbohydrate counting Understand insulin action times, dosing Emphasize need for frequent monitoring Pattern control: Daily insulin adjustments, modification based on BG patterns Correction factor what does an extra unit do for me? Impact of exercise Simple vs Complex Algorithm for Basal-bolus Approach 273 intent-to-treat patients where randomized to either a simple algorithm or a complex algorithm A1C was measured after 24 weeks Algorithm Δ from BL A1C % reaching A1C <7.% Simple Complex There were no significant differences in A1C reduction or A1C goal attainment found between the two groups Bergenstal RM, et al. Diabetes Care. 28;31(7): Simple Algorithm for Basal-bolus Approach Hypoglycemia Management Mean of last 3-day fasting SMBG mg/dl Adjustment >18 mg/dl Increase 8 units mg/dl Increase 6 units mg/dl Increase 4 units mg/dl Increase 2 units 7-94 mg/dl No change <7 mg/dl Insulin Glargine Adjustments: Both Groups Decrease by the same number of units as insulin glulisine; increase the titration week or up to 1% of the total insulin glargine dose SMBG = self-monitored blood glucose. Bergenstal RM, et al. Diabetes Care. 28;31(7): Mealtime dose Insulin Glulisine Adjustments: Simple Algorithm Groups Pattern of mealtime blood glucose values below target Pattern of mealtime blood glucose values above target 1 units Decrease by 1 unit Increase by 1unit units Decrease by 2 units Increase by 2 units 2 units Decrease by 3 units Increase by 3 units At-risk patients Ask about symptomatic and asymptomatic hypoglycemia at each encounter Preferred treatment glucose (15-2 g) After 15 mins of treatment, repeat if hypoglycemia continues (per SMBG) When SMBG normal: patient should consume meal or snack to prevent recurrence Prescribe glucagon if significant risk of severe hypoglycemia Hypoglycemia unawareness or episode of severe hypoglycemia Low or declining cognition Any form of glucose-containing carbohydrate can be used. American Diabetes Association. Diabetes Care. 214;37(suppl 1):S14-S8 Reevaluate treatment regimen Insulin-treated patients: raise glycemic targets for several weeks to partially reverse hypoglycemia unawareness and reduce recurrence Continually assess cognitive function with increased vigilance four hypoglycemia 4

5 Patients Reporting 1 Hypoglycaemic Event Per Year (%) Risk of Hypoglycemia Increases as Therapy Intensifies Strategies for Insulin Selection % For all therapies, the significance of differences between levels is P< % 7.9% 1.7%.8% Diet Alone MET SU Basal inslin only Basal + bolus insulin Treatment Strategy Convenience (once daily vs twice or three times daily) Proven safety: Analogs ORIGIN study showed low hypoglycemic risk, no adverse CV effects, and no cancer risk NPH a little more hypoglycemic risk than analogs Cost: NPH $ Analogs $$-$$$ Insurance coverage: Analogs coverage varies and may require prior authorization Wright AD, et al. J Diabetes Complications. 26;2: Summary of Comparative Insulin Trials Any insulin will lower glucose and A1C; the more injections, the better titration, and the higher the dose, the better the control All insulin use results in weight gain and increases the risk of hypoglycemia Generally, insulin analogs reduce the incidence of hypoglycemia over human insulins but generally do not result in better overall glycemic control Insulin strategies that include prandial dosing (eg, basal-bolus; premixed) will generally reduce A1C to a greater extent than basal-only, but at the expense of more weight gain, hypoglycemia Utilizing Non-insulin Therapies in Patients on Insulin Regimens to Improve Patient Outcomes Anne Peters, MD, FACP, CDE Director, Clinical Diabetes Program Professor, Keck School of Medicine University of Southern California Hirsch IB. N Engl J Med. 25; 352(2): Raskin P, et al. Diabetes Care. 25;28(2): Davidson MB, et al. Endocr Pract. 211;17: Fritsche A, et al. Diabetes Obes Metab. 21;12: Fonseca V, et al. Curr Med Res Opin. 21;26: Ilag LL, et al. Clin Ther. 27;29: Philis-Tsimikas A, et al. Clin Ther. 26;28: Riddle MC, et al. Diabetes Care. 23;26: Potential Non-insulin Therapies To be Combined with Insulin Metformin TZDs Pramlintide DPP-4 inhibitors SGLT2 inhibitors GLP-1 receptor agonists Study Metformin Plus Insulin: A1C Reduction Insulin and MET Mean (SD) Total Insulin (and PLB) Mean difference (95% CI), IV Weight (%) Mean difference (95% CI), IV Altuntas (4.4) (5.2) (-2.81 to 2.21) Favors insulin and MET Avilés-Santa (2.3) (1.2) (-2. to 1.8) Civera (1.2) (1.6) (-.4 to1.8) Douek (1.1) (1.) (-.51 to.11) Galani (1.1) (.5) (-1.9 to -1.1) Giugliano (.6) (.8) (-2.26 to -1.14) Hermann (.4) 16.3 (.6) (-1.73 to -1.7) Hirsch (1.8) (2.2) (-1.54 to.74) HOME (1.8) 196. (.8) (-.38 to -.2) Kabadi (4.) (2.9) (-2.73 to 3.33) Kokic (1.7) (1.3) (-1.58 to -.2) Kokic (1.6) (1.5) (-.88 to.8) Kvapil (3.6) (4.) ( to.92) Favors insulin (and PLB) Relimpio (2.2) 24.3 (1.7) (-3.5 to -.81) Schnack (1.8) (1.3) (-.88 to 1.8) SDDSa (1.1) (1.) (-1.33 to -.47) SDSSb (1.2) (.8) (-.97 to -.23) Strowig (1.) (1.1) (-.54 to.54) Ushakawa (1.6) (1.5) (-.53 to.33) Vähätalo (1.2) (2.1) (-1.2 to -1.62) Yilmaz (1.) (1.1) (-1.49 to -.11) Total (-1.49 to -.11) Test for heterogeneity: τ 2 =.29, x 2 = 11.65, df = 2, P<.1, I 2 =82%, Test for overall effect: z = 4.11, P<.1. Forest plot for changes in from baseline to end of follow-up. IV = inverse variance. CI = confidence interval. Random effects model used. Hemmingsen B, et al. BMJ. 212;344:e

6 Probability of hypoglycemia Metformin Plus Insulin: Weight Mean (SD) Total Insulin Insulin Mean difference Weight Mean difference Study and MET (and PLB) (95% CI), IV (%) (95% CI), IV Avilés-Santa (5.5) (4.7) (-5.76 to.36) Favors insulin and MET Civera (2.6) (2.8) (-3.42 to.82) Douek (2.1) (5.9) (-2.81 to -.19) HOME (2.5) (5.5) (-2.85 to -1.15) Kabadi (2.6) (4.) (-6.34 to -.6) Kvapil 26.8 (2.1) (6.2) (-2.4 to.44) Relimpio (.5) (1.9) (-1.7 to -.1) Schnack (3.1) (5.7) (-4.1 to 1.7) SDDSa (3.2) (6.3) (-4.35 to -.25) SDSSb (2.9) (5.8) (-4.5 to -.35) Strowig 22.5 (2.8) (4.3) (-5.75 to -2.5) Ushakawa (4.4) (5.1) (-1.51 to 1.11) Yilmaz (3.6) (3.) (-4.38 to -.2) Yki-Järvinen (5.2) (4.9) (-6.75 to -.65) Favors insulin (and PLB) Mild hypoglycemia Metformin Plus Insulin: Mild Hypoglycemia Douek 25 53/92 47/ (.86 to 1.45) Favors insulin and MET Hermann 211 2/16 / (.3 to ) Kvapil 26 13/116 1/ (.57 to 2.72) SDDSa /45 35/ (.76 to 1.22) SDSSb /45 43/ (.75 to 1.6) Ushakawa 27 6/1 4/ (.74 to 7.36) Yilmaz 27 2/17 2/ (.18 to 7.9) Total 148/ / (.85 to 1.2) Favors insulin (and PLB) Total (-22.2 to -1.13) Test for heterogeneity: τ 2 =.34, x 2 = 2.3, df = 13, P=.9, I 2 =36% Test for overall effect: z = 6., P<.1. Forest plot for changes in weight (kg) from baseline to end of follow-up. Random effects model used. Hemmingsen B, et al. BMJ. 212;344:e1771. Test for heterogeneity: τ 2 =.1, x 2 = 8.18, df = 6, P=.23, I 2 =27%, Test for overall effect: z =.12, P=.91. Forest plot for outcomes in severe hypoglycemia and mild hypoglycemia. M-H = Mantel-Haenszel. Random effects model used. Trial only reported hypoglycemia and did not specify severity. Hemmingsen B, et al. BMJ. 212;344:e1771. TZD Plus Insulin Pramlintide Plus Insulin Study Duration N Garg R et al 1 12 months Background therapy Intervention Δ From BL Δ From BL Weight (kg) 53 Insulin Rosiglitazone Strowig SM et al 2 4 months 88 Insulin Troglitazone Parameter Placebo + insulin (n=16) PRAML 6 ug TID + insulin (n=1) Mean Change from Baseline at Week Insulin use (%) PRAML 6 ug QID + Insulin (n=18) Weight (kg) Insulin dose reduction of 1-13 U was observed 1-2 pramlintide is only approved for use in combination with insulin P=.1. P<.1. 1 Garg R, et al. J Diabetes Complications. 27;21: Strowig SM, et al. Diabetes Care. 22;25: P<.5. Relative change from baseline. United States Food and Drug Administration. Available at: Accessed April 14, 214. DPP-4 Plus Insulin DPP-4 Inhibitor Plus Insulin: Hypoglycemia Vildagliptin Sitagliptin Alogliptin Saxagliptin Linagliptin Ref Number of patients Study duration (wk) Comparator Stable insulin Stable insulin Stable insulin Stable insulin Stable insulin Stable insulin Stable insulin 8.4 ± ± ± ± ± ± ±.1 Baseline.4.3 Linagliptin (+background basal insulin ± OAD) Placebo (+background basal insulin ± OAD) Change -.5 ± ± (-.7, -.5) -.6 (-.9, -.3) ± ±.1 Baseline placebo 8.4 ± ± ± ± ± ± ±.1 Change placebo -.2 ± ±.1 (-.1,.1) -.2 (-.5,.3) ± ±.1 Baseline 9.3 ± ± ± ± ± 3.9 NR 8.2 ± FPG (mmol/l) Change -.8 ± (-1.4, -.7) -1. (-2.7,-.2) -.6 ± ±.2 Baseline placebo 8.7 ± ± ± ± ± 4.3 NR 8.4 ± 2.6 Change placebo -.2 ± (-.6,.2) -1.3 (-1.8, -.5).3 ± ±.2 Hypoglycemia Hypoglycemia placebo Baseline 95 ± 2 78 ± ± ± ± ± 18 BMI (31 ± 5) Change 1.3 ± (-.2,.4) -.7 (-1.4, -.1).6 ± ±.1 Body weight (kg) Baseline placebo 95 ± 2 79 ± ± ± 1 91 ±.2 86 ± 16 BMI (31 ± 5) Change placebo.6 ± (-.3,.4) 1.1 (.2, 1.8).6 ± ± Time (days) Von WK, et al. Vasc Health Risk Manag. 213;9:

7 SGLT2 Inhibitors Plus Insulin GLP-1 RA + Insulin Options Study Deveineni D et al Duration 28 days Background Therapy Insulin ± 1 OAD Intervention 1 mg canagliflozin QD 3 mg canagliflozin BID Δ From BL Δ From BL Weight (kg) Diet, exercise, weight loss, oral agents + GLP-1 RA + Insulin Diet, exercise, weight loss, oral agents + Insulin + GLP-1 RA Not considered statistically significant. Devineni D, et al. Diabetes Obes Metab. 212;14(6): GLP-1 RA Plus Insulin Potential Benefits of Combining GLP-1-based Therapies with Insulin Promotes satiety and reduces appetite b cells: Enhance glucose-dependent insulin secretion a cells: Postprandial glucagon secretion Liver: glucagon reduces hepatic glucose output Stomach: Helps regulate gastric emptying Adapted from: Flint A, et al. J Clin Invest. 1998;11: Adapted from: Larsson H, et al. Acta Physiol Scand. 1997;16: Adapted from: Nauck MA, et al. Diabetologia. 1996;39: Adapted from: Drucker DJ. Diabetes. 1998;47: GLP-1-based therapies Insulin secretion (glucose-dependent) b-cell preservation Glucagon secretion (glucose-dependent) Risk of hypoglycemia Body weight PPG levels Energy intake Satiety GI tract motility Basal insulin therapy Insulin levels (insulin supplementation) b-cell rest Corrects glucotoxicity Relies on endogenous prandial insulin response Moderate risk of hypoglycemia Weight gain FPG levels Insulin/GLP-1 Combos Exenatide Added to Basal Glargine Screening Randomization Insulin glargine + OADs + EXE BID 5 μg EXE 1 μg EXE Study End Diet, exercise, weight loss, oral agents + GLP-1 RA + Insulin Insulin Glargine + OADs Insulin glargine + OADs + PLB BID Weeks of Treatment EXE = exenatide. PLB = placebo. Buse JB, et al. Ann Intern Med. 211;154(2):

8 Change in Change in Weight (kg) Statistical Comparisons A1C Change (%) Change in Body Weight (kg) LS mean ± SE Buse JB, et al. Ann Intern Med. 211;154(2): Exenatide Added to Basal Glargine 7.41 ±.9% 6.7 ±.9% % 18% 3% Weeks OG + EXE BID (Baseline 8.3.1%) OG + PLB BID (Baseline 8.5.1%) Exenatide Added to Basal Glargine OG + EXE BID (Baseline kg) 1 OG + PLB BID (Baseline kg) Weeks LS mean ± SE P<.1 between-treatment comparison Buse JB, et al. Ann Intern Med. 211;154(2): Exenatide Added to Basal Glargine: Side Effects Minor Hypoglycemia (n [%]) EXE BID PLB BID Overall incidence 34 (25%) 35 (29%) Rate (episodes/patient/year) Adverse Events (n [%]) Nausea 56 (41%) 1 (8%) Diarrhea 25 (18%) 1 (8%) Vomiting 25 (18%) 5 (4%) Headache 19 (14%) 5 (4%) Constipation 14 (1%) 2 (2%) One placebo patient experienced 2 episodes of major hypoglycemia No significant differences between groups; P<.5, between-group comparison Buse JB, et al. Ann Intern Med. 211;154(2): MET + LIRA + Insulin Detemir. MET + LIRA 1.8 mg MET + LIRA 1.8 mg + IDet Observational MET + LIRA 1.8 mg Run-in Phase Randomized Phase (weeks 12 to ) (weeks to 26) Mean (2SE); data are from the full analysis set (FAS) no imputation IDet = insulin detemir. LIRA = liraglutide. DeVries JH, et al. Diabetes Care. 212;35: Liraglutide with Basal Insulin Over 38 Weeks After MET + LIRA Run-in Efficacy MET + LIRA + Idet (n=162) MET + LIRA (n=161) At 38 Weeks Weight Change After MET + LIRA Run-in At 38 Weeks Minor hypoglycemia (EPY).3 EPY = events/patient-year No major hypoglycemia in any group during weeks Transient nausea in 21% during weeks -12, 4% during weeks DeVries JH, et al. Diabetes Care. 212;35: Patients with T2DM (n=1663) Insulin Degludec + Liraglutide Combination Ideg + LIRA OD + metformin ± pioglitazone (n=834) IDeg OD + metformin ± pioglitazone (n=414) Liraglutide OD (1.8 mg) + metformin ± pioglitazone (n=415) 26 Weeks Randomized 2:1:1 Open label Mean Fasting PG Titration algorithm: IDegLira and Ideg. Singapore, age 21 years. Buse J. Presented at: The 73rd American Diabetes Association Scientific Sessions; June 21-25, 214; Chicago, IL. Inclusion criteria T2DM Insulin-naïve, treated with metformin ± pioglitazone A1C 7.-1.% BMI 4kg/m 2 Age 18 years Dose Change Mg/dL Mmol/L Dose steps or U <72 < <9 <

9 Change in Body Weight Between Baseline and End of Trial (kg) FPG (mmol/l) FPG (mg/dl) Change in Body Weight Over Time (kg) Mean Cumulative Episodes Per Subject IDeg + LIRA Combination: Glycemia A1C Over Time FPG Over Time LIRA (n=414) LIRA (n=414) IDeg (n=413) IDeg (n=413) IDeg + LIRA (n=833) IDeg + LIRA (n=833) FPG EOT 32 mg/dl 131 mg/dl A1C EOT -1.28% 7.% % 6.9% -65 mg/dl 14 mg/dl mg/dl 1 mg/dl -1.91% 6.4% Mean values (±SEM) based on FAS and LOCF-imputed data. Mean values (±SEM) based on FAS and LOCF-imputed data. --- ADA/EASD A1C target <7.%. AACE A1C target 6.5%. EOT = end of trial. FAS = full analysis set. LOCF = last observation carried forward Buse J. Presented at: The 73rd American Diabetes Association Scientific Sessions; June 21-25, 214; Chicago, IL. IDeg + LIRA Combination: Body Weight and Hypoglycemia Change in Body Weight Over Time LIRA (n=414) IDeg (n=413) IDeg + LIRA (n=833) Mean values (±SEM) based on FAS and LOCF-imputed data. Estimated treatment differences and P-values are from ANCOVA kg P= kg P=.1. Confirmed Hypoglycemia 1.4 LIRA (n=412) SAS = statistical analysis system. Buse J. Presented at: The 73rd American Diabetes Association Scientific Sessions; June 21-25, 214; Chicago, IL IDeg (n=412) IDeg + LIRA (n=825) A1C 6.9% 6.4% 7.% Mean values based on SAS. Estimated rate ratio and P-values are from a negative binomial model. Rate ratio:.68 P=.2 Rate ratio: 7.61 P=.1 Adding Incretin-based Therapies to Insulin: Weight Conclusions In patients with T2DM, treating the multiple defects (insulin resistance plus insulin deficiency) can improve A1C levels Options include adding metformin, DPP-4 inhibitors, GLP-1 RAs, pramlintide, TZDs and potentially SGLT2 inhibitors Must adjust the dose of insulin in order to avoid hypoglycemia when adding some of the non-insulin agents Copyright 211 American Diabetes Association, Inc Vora J. Diabetes Care. 213;36:S226-S232. 9