Drug List. Drug List (cont.) Objectives. Case 1 Bruce. Presenter Disclosure Information

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1 1:15 :3 PM GLP-1 Receptor Agonists and Basal Insulin Combination: A Complementary Strategy for Type Diabetes Treatment Intensification SPEAKERS Vivian Fonseca, MD Dace Trence, MD, FACE Presenter Disclosure Information The following relationships exist related to this presentation: Vivian Fonseca, MD: Speaker's Bureaus for AstraZeneca; Novo Nordisk Inc.; Sanofi US. Advisory Boards for Amgen; AstraZeneca; Janssen Pharmaceuticals, Inc.; Lilly; Novo Nordisk Inc.; Sanofi US; Takeda Pharmaceuticals U.S.A., Inc. Contracted Research for Asahi Kasei Pharma America ; Bayer; GI Dynamics, Inc.; and Gilead Sciences Medical Affairs. Ownership Interest (e.g. stocks, stock options etc.) in MicroBiome Therapeutics. Dace Trence, MD, FACE: Ownership Interest (e.g., stocks, stock options, etc.) in Medtronic, Inc. and Sanofi US. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Drug List Drug List (cont.) Generic Drug Name albiglutide allopurinol atorvastatin bromocriptine dulaglutide exenatide/exenatide ER glimepiride hydrochlorothiazide (HCTZ) insulin aspart US Trade Name Tanzeum Zyloprim Lipitor Cycloset Trulicity Byetta/Bydureon Amaryl Microzide Novolog Generic Drug Name insulin detemir insulin degludec insulin glargine insulin glulisine insulin lispro lisinopril liraglutide metformin nateglinide repaglinide US Trade Name Levemir Tresiba Lantus Apidra Humalog Prinivil, Zestril Saxenda/Victoza Glucophage Starlix Prandin Objectives Apply current ADA/EASD recommendations for setting A1C and glucose targets and timely intensification of therapy in patients with type diabetes Compare and contrast the clinical profiles of the different GLP-1 receptor agonists and assess their utility in reducing postprandial glucose Evaluate current data on fixed-ratio combinations of GLP-1 RAs and basal insulin for the treatment of type diabetes Formulate evidence-based treatment regimens that optimize control of both fasting and postprandial glucose in patients requiring therapy intensification Case 1 Bruce Bruce is a 56-year-old man who presents for evaluation of fatigue and progressively increasing nocturia. Suspects prostate acting up Medical history includes hypertension, dyslipidemia, gout Current meds: ACE inhibitor, thiazide, statin, allopurinol Physical exam: weight 4 lbs, BMI 36, BP 18/77, abdominal obesity

2 Case 1 Bruce cont d On further questioning, he reported that he lost pounds in the past 3 months, and it was surprisingly easy. He also noted some blurry vision, but his optometrist just recommended reading glasses. Case 1 Bruce s Lab Results Random serum glucose: 6 mg/dl Hemoglobin A1C: 7.8% Bruce is diagnosed with type diabetes Family history significant for diabetes in mother and older brothers. Nutrition: Helpful Advice Portion size review; use plate method Snack choices Decreased soft drink and fruit juice intake Volumize carbohydrate meals with vegetables, cutting down on carbohydrate, but increasing satiety Courtesy of Dace Trence, MD. Weight at 1 Months (kg) Adherence Is More Important Than Diet Type for Weight Loss Success Atkins Weight Change by Diet Type Dansinger M. JAMA. 5;93: Zone Weight Ornish Watchers Weight Change by Dietary Adherence r =.7, p =.4 15 r =.6, p < Mean adherence score over 1 year Atkins Zone Weight Watchers Ornish Case 1 Bruce cont d Goes to diabetes education Starts walking every other day and loses 14 pounds Starts monitoring his glucose levels Blood sugars fasting mg/dl, and premeal blood sugars mg/dl A1C now % Normoglycemia and Recommended Glycemic Targets in TDM Glucose Control Healthy Individuals 1 A1C, %* <6. <7. Preprandial PG, mg/dl Peak postprandial PG, mg/dl ADA 16 1 ADA & AACE 16 Individualized Target* <7.% most pts 1 % healthy pts 3 < <14 <18 a <14-18 b a. Peak postprandial capillary plasma glucose; b. -hour postprandial glucose concentration. *A1C of 7 8% is reasonable in patients with known CVD or multiple co-morbidities. PG = plasma glucose; ADA = American Diabetes Association. 1. ADA. Diabetes Care. 16;39(Suppl. 1):S1 S11.. ADA. Diabetes Care. 1;4: Garber AJ, et al. Endocr Pract. 16;:

3 !!! Individualizing A1C Targets for Patients with TDM Most Intensive Less Intensive Least Intensive 6.% 7.% 8.% Highly motivated, adherent, knowledgeable, excellent self-care capacities, and comprehensive support systems Low Moderate Psychosocioeconomic Considerations Less motivated, non-adherent, limited insight, poor self-care capacities, and weak support systems Hypoglycemia Risk High Patient Age Which Agent to Use? Do Guidelines Provide Direction? Disease Duration 5 15 Other Co-morbidities Multiple/Severe None Few/Mild Established Vascular Complications None Cardiovascular Disease None Early Micro Advanced Micro Data from Ismail-Beigi F, et al. Ann Intern Med. 11;154(8): ADA/EASD 16 Guidelines ADA/EASD 16 Guidelines cont d Dual Therapy SU DPP-4-I SGLT-i GLP-1 RA Insulin (basal) Initial drug monotherapy Efficacy ( A1C) Hypoglycemia Weight Side effects Costs Healthy eating, weight control, increased physical activity Metformin low risk neutral / loss GI / lactic acidosis low If needed to reach individualized A1C target after ~3 months, proceed to -drug combination (order not meant to denote specific preference) Efficacy ( A1C): Hypoglycemia: Weight: Major side effect(s): Costs: Triple Therapy intermediate intermediate est moderate risk low risk low risk low risk low risk risk gain gain neutral neutral loss gain hypoglycemia edema, HF, fxs rare GUIs, DKA GI hypoglycemia low variable If needed to reach individualized A1C target after ~3 months, proceed to 3-drug combination (order not meant to denote specific preference) SU+ + DPP-4-I + SGLT-i + GLP-1 RA + Insulin (basal) + SU SU SU or DPP-4-i or DPP-4-i or or SU or DPP-4-i or SGLT-i or SGLT-i or SGLT-i or DPP-4-i or or SGLT-i or GLP-1-RA or GLP-1-RA or Insulin or Insulin or Insulin or GLP-1-RA or Insulin or Insulin If A1C target not achieved after ~3 months of triple therapy and patient: (1) on oral combination, move to injectables, () on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1 RA or mealtime insulin. In refractory patients consider adding or SGLT-i. Combination injectable therapy Basal Insulin + Mealtime insulin or GLP-1 RA Adapted from American Diabetes Association. Diabetes Care. 15;38(suppl 1):S41-S48. DPP-4-i = dipeptidyl-deptidase 4 inhibitor; SGLT-i = sodium-glucose cotransporter inhibitor; GLP-1 RA = glucagon-like peptide-1 receptor agonists; GUI = genitourinary infections; DKA = diabetic ketoacidosis. Adapted from American Diabetes Association. Diabetes Care. 16;39(Suppl. 1):S1 S11. AACE: Glycemic Control Algorithm for TDM Entry A1C < % Monotherapy* MET GLP-1 RA SGLT- i DDP-4 i AGi SU/GLN If not at goal in 3 months, proceed to Double Therapy MET or other first-line agent + Entry A1C % Dual Therapy* If not at goal in 3 months, proceed to Triple Therapy Lifestyle Modification (including Medically Assisted Weight Loss) GLP-1 RA SGLT- i DPP-4 i Basal Insulin Colesevelam Bromocriptine QR AGi SU/GLN MET or other first-line agent + secondline agent *Order of medications listed represents a suggested hierarchy of usage. Garber AJ, et al. Endocr Pract. 16;: Progression of Disease Triple Therapy* GLP-1 RA SGLT- i Basal Insulin DPP-4 i Colesevelam Bromocriptine QR AGi SU/GLN If not at goal in 3 months, proceed to or intensify insulin therapy Entry A1C > 9.% No Dual Therapy OR Triple Therapy Symptoms Yes Insulin ± Other Agents Add or Intensify Insulin Refer to Insulin Algorithm Few adverse events or possible benefits Use with caution Case 1 Bruce cont d You recommend starting metformin. Bruce reports diarrhea; you suggest switching to extended-release. A1C drops to 6.9% at 3-month follow-up. Bruce maintained good glycemic control for about years on metformin alone, then glimepiride was added. One year after adding the glimepiride, Bruce reports his job has changed to involve considerable travel. You note his weight is up 5 lbs. Fasting blood sugars have bumped up to mg/dl, but postprandial glucose is stable A1C now 8.1%.

4 UKPDS: Progressive Deterioration in Glycemic Control Over Time Basal Insulin in Type Diabetes When to consider 9 A1C Level 1 B-cell Function When combination oral/injectable agents become inadequate (A1C >% or er) High FPG >15 mg/dl Median A1C (%) Conventional Intensive Time from Randomization (y) Years from Diagnosis 1. UKPDS Group. Lancet. 1998;35: Holman RR. Diabetes Res Clin Pract. 1998;4(suppl):S1-S5. b-cell Function (%) Unacceptable side effects of other agents Severely uncontrolled* To be effective, basal insulin plus oral agents require presence of some endogenous B-cell function (oral agents are not effective in T1DM) FPG = fasting plasma glucose; PPG = postprandial glucose. *Defined as fasting glucose > 5 mg/dl, random glucose > 3 mg/dl, A1C > %, ketonuria, or symptomatic (polyuria, polydipsia, and weight loss) by ADA 9 Consensus Statement. After glucose is controlled, oral agents can be added and insulin withdrawn if preferred. Nathan DM, et al. Diabetes Care. 9; volume 3, Inzucchi SE, et al. Diabetes Care. 1;35(6): ADA Diabetes Care. 14:37(suppl 1):S14-S8. Basal Insulin The Simple Way to Add Insulin Bedtime or morning long-acting insulin OR Bedtime intermediate-acting insulin Daily dose: U or.1. U/kg Check FPG daily Initiate insulin with a single injection of a basal insulin Case 1 Bruce Follow-up: Bruce returns 3 months later, and he is feeling much better. He has up-titrated his basal insulin dose from to 6 units every night. His meter download shows fasting glucose 1 mg/dl over the past several weeks. Adjust dose 15% or 4 U once to twice weekly to reach FPG target 8 13 mg/dl Continue regimen and check A1C every 3 months In the event of hypoglycemia or FPG level <7 mg/dl, reduce insulin dose by 4 U or % His A1C is now 7.%. You congratulate and acknowledge his progress, and ask him to come back in 3 months. Inzucchi S, et al. Diabetes Care. 15;38: Case 1 Bruce Follow-up cont d: Bruce returns in 5 months because he missed his last appointment. He reports that his job has required even more travelling. His fasting blood sugars have continued in the 13 mg/dl range, but postprandial glucoses are now in the 19 mg/dl range. His A1C is rechecked; now at 8.%. Physiologic (Basal-Bolus) Insulin Treatment Matching Insulin Administration to Insulin Needs μu/ml Bolus insulin B L D Basal insulins Normal pattern Time of Day B = breakfast; L = lunch; D = dinner. Adapted from Polonsky KS, et al. N Engl J Med. 1988;318:131-9.

5 ADA Recommendations for Advancing Insulin # INJECTIONS COMPLEXITY 1 Basal Insulin LOW (usually with metformin ± other noninsulin agent) FLEXIBILITY: If not controlled after FBG target is reached (or if dose >.5 U/kg/day), treat PPG excursions with mealtime insulin. (Consider initial GLP-1-RA trial) MOD Add 1 rapid insulin injection Change to before largest meal premixed insulin twice daily If not controlled, Add rapid insulin If not controlled, 3+ consider Injections before meals consider HIGH basal-bolus ( basal-bolus ) basal-bolus MORE FLEXIBLE LESS FLEXIBLE Basal Plus Mealtime Insulin Use rapid-acting analogs (Aspart, Lispro, Glulisine), not regular insulin Easier timing, less postprandial hypoglycemia Start with 1 injection at largest meal: 4 units and titrate, OR By weight:.1 U/kg Titrate to: <14 mg/dl hours postprandial OR <1 mg/dl next meal or bedtime Consider a decrease or stopping oral secretagogues when prandial insulin is started Can continue metformin,, AGI, GLP-1, DPP-4 inhibitor Basal bolus dosing ~5% bolus insulin and ~5% basal insulin ADA. Diabetes Care. 15;38(suppl 1):S41-S48. Garber AJ, et al. Endocr Pract. 16;: Case 1 Bruce Follow-up cont d: Mealtime insulin of units was added with his largest meal. His basal insulin was reduced to 5 units at bedtime and glimepiride was discontinued. At 3-month follow-up, his A1C was 6.8%. Over the next year Bruce continues to maintain good glycemic control, but did report a couple minor episodes of hypoglycemia. His weight has also increased. Bruce asks if there is anything that can be done to lower his risk of hypoglycemia. His current meds are metformin, mealtime insulin units and basal insulin 5 units. His current A1C is 7.4%. He says he periodically skips his insulin dose to avoid hypoglycemia. Addition of Exenatide to Insulin Glargine Change in A1C (%) Basal insulin was decreased % initially if A1C was <8.%. Basal was titrated, and dose was greater in placebo group. No increase in hypoglycemia. A1C A1C 7.% Weight -1.7 * -1. Patients Reaching Target (%) Data are mean. *Significant vs placebo. Buse JB, et al. Ann Intern Med. 11;154: p <.1 * 6 Insulin Glargine + Exenatide ± OADs (n = 137) Insulin Glargine + Placebo ± OADs (n = 1) 35 Change in Body Weight (kg) A1C (%) Insulin (IU) Liraglutide Added to Basal Insulin Liraglutide A1C 1.3% Insulin dose 11% Time since Randomization (weeks) Change in A1C (%) Ratio to Baseline in Insulin Dose FPG (mmol/l) Body Weight (kg) Placebo FPG 3.5 mg/dl Weight 3.1 kg Time since Randomization (weeks) Change in FPG (mmol/l) Change in Body Weight (kg) Case 1 Bruce Follow-up cont d: Mealtime insulin was discontinued. Bruce was advanced to liraglutide 1.8 mg daily, and his basal insulin was titrated to 44 units at night. At 6-month follow-up, his A1C was 6.9%, and he has not experienced any episodes of hypoglycemia. He reports a weight loss of 5 pounds. Basal insulin was decreased % if A1C was < 8.%. No up-titration of basal insulin allowed. Ahmann A, et al. Diab Obes Metab. 15;17:56-64.

6 Metformin mg bid Glimepiride 4 mg qd Glargine U, 68 units hs Case Ann Ann is a 64-year-old woman with a 14- year history of type diabetes. She is active and works full time. Had been treated with metformin and glimepiride until bedtime insulin glargine was started 4 years ago. The dose was increased intermittently over the years. PMH: Hypertension, hyperlipidemia Medications: Lisinopril mg qd Atorvastatin 4 mg qd HCTZ 1.5 mg qd PE: Case Ann cont d BMI = 33.6 BP = 136/8 Central obesity Decreased vibratory sensation and monofilament sensation in feet Lab tests: A1C = 8.% Creatinine =.89 mg/dl Glucose monitoring: LDL = 78 mg/dl infrequent (<1x daily) average = 15 mg/dl Relative Contribution of FPG and PPG to A1C Fasting glucose Postprandial glucose Case Ann cont d Ann agrees to monitor for 5 days before meals and bedtime Contribution (%) % 7% 5% 5% 55% 45% 6% 4% 7% 3% < 7.3% % 9.% 9.3.% >.% n=58 n=58 n=58 n=58 n=58 A1C Quintiles Mean glucose values: Breakfast 138 mg/dl Lunch 1 mg/dl Dinner 184 mg/dl Bedtime 18 mg/dl Monnier L, et al. Diabetes Care. 3;6: Adding Prandial Insulin to Basal Advantages Treats postprandial hyperglycemia Increases success rate in achieving A1C < 7% compared to oral agents More effective than oral agents Disadvantages Increases weight gain Increases hypoglycemia risk Less convenient with multiple injections Combination of Basal Insulin with a GLP-1 RA Has a Scientific Logic Basal insulin analogs Simple to initiate Control nocturnal and FPG Lower hypoglycemia risk vs NPH Modest weight increase (1 to 3 kg) Achieve A1c targets in ~5-6% Complementary actions GLP-1 RAs Additive actions Simple to initiate Pronounced PPG control (especially short-acting agents) No increase in hypoglycemia Weight lowering/neutral effects Achieve A 1c targets in ~4-6% Little S, et al. Diabetes Technol Ther. 11:13(suppl 1):S53-S64. Cohen ND, et al. Med J Australia. 13;199(4): Carris NW, et al. Drugs. 14;74(18):

7 Pharmacokinetic Profile of GLP-1 RAs Drug Dosing Half-life Duration of Action Exenatide 5 mcg SC twice daily.4 hours Short-acting Lixisenatide mcg SC daily 4 hours Short-acting Albiglutide 3 5 mg SC once weekly 6 7 days Long-acting Dulaglutide mg SC once weekly 5 days Long-acting Exenatide ER mg SC once weekly.4 hours Long-acting Liraglutide mg SC once daily 13 hours Long-acting Some General Characteristics of GLP-1 Receptor Agonists Short-acting agents (exenatide, lixisenatide) Have greater effect on postprandial glucose Possibly more nausea Long-acting agents (albiglutide, exenatide ER, dulaglutide, liraglutide) Less effect on postprandial glucose but greater fasting glucose reduction May have variable efficacy and weight loss Albiglutide appears to have lower efficacy and less weight loss but has proven effective in combination with basal insulin ER = extended release. Pinelli NR and Hurren KM. The Annals of Pharmacotherapy. 11;45(7-8): American Diabetes Association. Diabetes Care. 15;38(suppl 1):S41-S48. US FDA. Drugs@FDA Website. data.fda.gov/scripts/cder/drugsatfda/. EU EMA. Medicines@EMA Website. Considerations for GLP-1 RAs Renal impairment Reduced clearance of exenatide Exenatide should not be used in patients with severe renal impairment or ESRD (CrCl<3 ml/min) Hypovolemia due to nausea and vomiting Pancreatitis No causal relationship confirmed Not for use in patients with history of pancreatitis Educate patients about signs and symptoms; stop therapy if signs and symptoms present Do not restart therapy if pancreatitis is confirmed Personal or family history of MTC or MEN Contraindicated ESRD = end-stage renal disease; MTC = medullary thyroid carcinoma; MEN = multiple endocrine neoplasia syndrome type. Linnebjerg H, et al. Br J Clin Pharmacol. 7;64: Egan AG, et al. N Engl J Med. 14;37(9): Exenatide, liraglutide, albiglutide and dulaglutide at Accessed April, 6. Postprandial Glucose Effect of Short- and Long-Acting GLP-1 RAs: EXN vs. LIRA EXN twice daily preferentially affects PPG compared to liraglutide. EXN twice daily reduced PPG significantly more after breakfast and dinner than LIRA, p<.1 Self-Measured Plasma Glucose (mmol/l) Before BF * p <.1 BF + 9 min Before Lunch Lunch + 9 min Time Before Dinner Dinner Bedtime + 9 min PPG = postprandial glucose; BF = breakfast; EXN = exenatide; LIRA = liraglutide. Buse JB, Rosenstock J, Sesti G, et al. Lancet. 9;374: * p <.1 LIRA Baseline LIRA Week 6 EXN Baseline EXN Week 6 PPG Effect of Short- and Long-Acting GLP-1 RAs: LIXI vs LIRA Mean Change from Premeal Plasma Glucose (mg/dl) Lixisenatide (Baseline) Liraglutide (Baseline) Meal p < Time after Study Drug Administration GLP-1 Agonist LIXI = lixisenatide; PPG = postprandial glucose. Kapitza C, et al. Diabetes Obes Metab. 13;15(7):64-9. Lixisenatide (Day 8) Liraglutide (Day 8) Patients (%) Proportion of Patients with -h PPG < 14 mg/dl at Day Lixisenatide Liraglutide (n = 75) (n = 68) Exenatide + Basal Insulin as an Alternative to Prandial Insulin + Basal Insulin Adding Exenatide bid to Insulin 1,,a Basal Insulin + Prandial Insulin + MET Basal INS + EXN ± MET (n = 5) (n = 5) P <.1 Chane in A1C from Baseline (%) %.9% Change in Weight from Baseline (kg) Glycemic variability (MAGE) was improved in the EXN bid group but not in the prandial insulin group. No severe hypoglycemia events reported in either group. a. EXN administered at -3 meals daily, prandial insulin administered at 3 meals daily 1 1. FLAT-SUGAR Trial Investigators. Diabetes Care. 15;38: Hirsch IB, et al. Diabetes. 15; 64(suppl 1):A [abstract 385-OR]

8 Albiglutide as an Alternative to Prandial Insulin to Intensify Basal Insulin Chane in A1C from Baseline (%) GLAR + ALBI ± MET ± PIO ± AGI (n = 85) %.6% Change in Weight from Baseline (kg) GLAR + LIS TID ± MET ± PIO ± AGI (n = 81) Documented symptomatic hypoglycemia was more frequent in the lispro group;.3 vs.9 events/pt/y (p value not reported).8 P <.1 Total Hypoglycemia (%) % 38.1% ALBI = albiglutide; GLAR = glargine; LIS = lispro; MET = metformin; PIO = pioglitazone; AGI = alpha-glucosidase inhibitor. Rosenstock J, et al. Diabetes Care. 14;37: Change in A1C (%) Lixi/Basal vs Basal/Plus, Basal/Bolus: Change in A1C Insulin Glargine ± Metformin % 7.9% 7.8% 7.8% 7.7% Insulin Glargine ± Lixisenatide QD OR Insulin Glulisine QD OR Insulin Glulisine TID Lixisenatide QD + Insulin Glargine (n=97) Insulin Glulisine QD + Insulin Glargine (n=98) Insulin Glulisine TID + Insulin Glargine (n=95) Lixisenatide QD + Insulin Glargine non-inferior to Insulin Glargine + Insulin Glulisine TID Week 6 (LOCF) Screening Baseline Time (weeks) QD = daily; TID = three times daily; LOCF = last observation carried forward. Rosenstock J, et al. Diabetes Care. 16;39: % 7.% 7.% Change in Body Weight (kg) Lixi/Basal vs Basal/Plus, Basal/Bolus: Change in Weight Lixisenatide QD + Insulin Glargine Insulin Glulisine QD + Insulin Glargine Insulin Glulisine TID + Insulin Glargine Lixisenatide QD + Insulin Glargine significantly reduce weight compared to Insulin Glargine + Insulin Glulisine TID Baseline Time (weeks) Diff = difference. Rosenstock J, et al. Diabetes Care. 16;39: Week 6 (LOCF) Diff. of -. kg P<.1 Response Rate (%) n = 3.% NS 5.% NS A1C <7% and no documented symptomatic hypoglycemia 13.5% P< % P<.5 Efficacy and Safety A1C <7% and no wt. gain 3.% P<.5 3.% P<.5 A1C <7% no wt. gain, no documented symptomatic hypoglycemia HHypoglycemia Rate (Events by hour) wt = weight. Rosenstock J, et al. Diabetes Care. 16;39: Lixisenatide QD + Insulin Glargine (n=98) Insulin Glulisine QD + Insulin Glargine (n=31) Insulin Glulisine TID + Insulin Glargine (n=94) 3: <6: Events at Week 6 6: : 14: <: <14: <18: Time Period 18: <3: Benefits of Adding a GLP-1 RA to Basal Insulin as Compared with Adding Prandial Insulin Fewer injections Weight loss Lower hypoglycemic risk Reduce insulin doses Postprandial benefit, particularly with short-acting agents Case Ann Follow-up In addition to her current meds, Ann was started on lixisenatide mcg once daily to better manage her postprandial hyperglycemia. At 1-month follow-up, her A1C is 6.9%. Carris NW, et al. Drugs. 14;74(18):

9 Efficacy of Fixed-Ratio iglarlixi* in Insulin Naïve TDM Patients TDM patients not controlled on Met ± second OAD Mean A1C (%) % 8.1% Mean iglarlixi (N = 469) Difference p-value -.78% <.1 vs Lixi (N = 34) vs Glargine (N = 467) -.9% <.1 iglarlixi Glargine Lixi % Screening Baseline Week Lixi Glargine iglarlixi A1C <7.% with No Wt Gain and No Symptomatic *Not FDA approved. p <.5. p <.1. iglarlixi = fixed-ratio insulin glargine/lixisenatide; OAD = oral antidiabetic agent. Hypoglycemia RosenstockJ, Aronson R, Grunberger G, et al. Diabetes Care. 16 Aug 15. pii: dc [Epub ahead of print] 7.3% 6.8% Percent Patients (%) (%) % Patients with A1C < 7.% at Week 3 Fixed-Ratio iglarlixi* in Insulin Naïve TDM Patients: Glucose and Weight Effects Mean Change from Baseline (mg/dl) FPG p <.1 -h PPG Excursions p <.1 *Not FDA approved PPG changes are mean for all 3 meals. Rosenstock J, Aronson R, Grunberger G, et al. Diabetes Care. 16 Aug 15. pii: dc [Epub ahead of print] iglarlixi (N = 468) Glargine (N = 466) Lixi (N = 33) With iglarlixi, nausea that occurred mostly over the first 6-8 weeks was the most common (%) side effect, which is significantly less than Lixi alone (4%) -3. Weight Change (kg) p < Mean A1C (%) Efficacy of Fixed-Ratio iglarlixi* in TDM Patients Not Controlled on Basal Insulin TDM patients not controlled on basal insulin + Met ± nd OAD % 8.1% iglarlixi (N = 366) vs Glargine (N = 365) Mean Difference p-value -.5% <.1 iglarlixi 55 Glargine 4 6.9% Screening Baseline Week Glargine iglarlixi A1C < 7.% with No Wt Gain and No Symptomatic Hypoglycemia *Not FDA Approved iglarlixi Briefing Document. Accessed May 5, 16. (Results not yet validated under FDA review.) % Percent Patients (%) (%) % Patients with A1C < 7.% at Week 3 Mean Change from Baseline (mg/dl) Fixed-Ratio iglarlixi * in TDM Patients Not Controlled on Basal Insulin: Glucose and Weight Effects FPG p = NS -8.3 iglarlixi (N = 366) -h PPG Excursions Glargine (N = 365) *Not FDA Approved PPG changes are mean for all 3 meals. iglarlixi Briefing Document. Accessed May 5, 16. (Results not yet validated under FDA review.) -8.4 p < Weight Change (kg) -.7 p <.1 Efficacy of Fixed-Ratio IDegLira* in Insulin Naïve TDM Patients not Controlled on OADs A1C (%) Deg/Lira was superior (p<.1) to Lira and non-inferior to insulin Deg in reducing A1C A1C over Time LIRA (n=414) IDeg (n=413) IDegLira (n=833) 7.% 6.9% FPG over Time LIRA (n=414) IDeg (n=413) IDegLira (n=833) Time (weeks) Time (weeks) OADs = metformin ±pioglitazone; LIRA = liraglutide; IDeg = insulin degludec; IDegLira = fixed-ratio insulin degludec/liraglutide. *Not FDA Approved. Gough SC, et al. Lancet Diabetes Endocrinol. 14;: % FPG (mg/dl) Deg/Lira significantly reduced FPG compared to Lira (p<.1) 131 mg/dl 4 mg/dl mg/dl Fixed-Ratio IDegLira in Insulin Naïve TDM Patients: Glucose and Weight Effects Mean Change in FPG From Baseline (mg/dl)* IDegLira (N=71) IDeg (N=38) Liraglutide (N=38) Hypoglycemia rate: IDegLira vs LIRA: rate ratio 7.61, p<.1 IDegLira vs IDeg: rate ratio.68, p=.3 Mean Change in PPG Increment (mg/dl)* p=.9 Mean treatment difference in Wt.: IDegLira vs IDeg: -. kg, p<.1 IDegLira vs LIRA: +.44 kg, p<.1 *Mean change from baseline at wk 6 in PPG increment across all meals based on continuous glucose monitoring data. Not FDA Approved. Gough SC, et al. Lancet Diabetes Endocrinol. 14;: NDA 8583 Briefing Document. Accessed May 5, 16 (Results not yet validated under FDA review)

10 Efficacy of Fixed-Ratio IDegLira* in TDM Patients Not Controlled on Basal Insulin A1C (%) TDM patients not controlled on basal insulin + met ± SU or glinides Time (weeks) = -1.5%, p<.1 IDegLira (N=199) IDeg (N=199) *Not FDA Approved NDA 8583 Briefing Document. Accessed May 5, 16 (Results not yet validated under FDA review). (%) % Patients with A1C <7.% at Wk 6 IDegLira p<.1 IDeg Mean Change from Baseline in FPG (mg/dl) Fixed-Ratio IDegLira * in TDM Patients Not Controlled on Basal Insulin: Glucose and Weight Effects p<.1-3. IDegLira (N=199) IDeg (N=199) Nausea was most common side effect with IDegLira (7.8%) which occurred mostly over the first 6 weeks which is significantly less than LIRA alone (15.1%) *Not FDA Approved NDA 8583 Briefing Document. Accessed May 5, 16 (Results not yet validated under FDA review). Change in Weight (kg) p<.5 When Basal Is Not Enough Basal Bolus Add Prandial Insulin before Each Meal Basal Plus Add Prandial Insulin at Main Meal Basal Add Basal Insulin and Titrate Basal plus GLP-1 RAs Lifestyle Changes plus Metformin (± other agents) Summary Type diabetes is characterized by progressive beta cell dysfunction requiring advancing therapy. Following one or two oral agents, GLP-1 receptor agonists or basal insulin are equally effective agents. When the combination of oral agents and basal insulin fails, the problem is often postprandial hyperglycemia. In TDM, when glucose control is lost after basal insulin, GLP-1 receptor agonists often hold advantages over rapid-acting insulin analog therapy. Premixed basal insulin with a GLP-1 receptor agonist in a single injection may be useful in the future. Questions?