June 5th, Pennsylvania Convention Center 1101 Arch St Philadelphia, PA 19107

Transcription

1 June 5th, 214 Pennsylvania Convention Center 111 Arch St Philadelphia, PA 1917 Dace Trence, MD, FACE Director, Diabetes Care Center Professor, Division of Metabolism, Endocrinology and Nutrition University of Washington Medical Center Seattle, Washington Dawn Smiley, MD Associate Professor of Medicine Emory University School of Medicine

2 Session 9: Insulin Therapy in Patients With Type 2 Diabetes: Current and Emerging Basal Insulins Learning Objectives 1. Outline the benefits of early insulin therapy in patients with type 2 diabetes. 2. Discuss when insulin may be initiated for the treatment of patients with type 2 diabetes. 3. Describe the advantages and disadvantages of various insulin regimens and apply them in clinical practice for the selection and titration of insulin in patients with type 2 diabetes. 4. Identify the barriers to insulin-mediated glucose control and apply strategies to overcome them. 5. Describe how improved pharmacokinetic and pharmacodynamic profiles of emerging insulins may reduce hypoglycemia and optimize insulin administration. Faculty Dace L. Trence, MD, FACE Professor, Division of Metabolism, Endocrinology and Nutrition Director, Diabetes Care Center University of Washington Medical Center Seattle, Washington Dr Dace Trence is currently director of the Diabetes Care Center and a professor of medicine at the University of Washington Medical Center in Seattle. She is director of the University of Washington Endocrine Fellowship program, as well as director of Endocrine Days, a medical education program for endocrinologists practicing in the Pacific Northwest. Her current interests include improving educational processes in diabetes self management and clinical training of health care professionals. Dr Trence currently serves on the American Association of Clinical Endocrinologists (AACE) board of directors, chairing the AACE publications committee and co-chairing the AACE CME committee. She has served on the editorial boards of several journals, including Clinical Diabetes. Dr Trence has published articles in the Journal of Clinical Endocrinology & Metabolism, the Journal of the American Medical Association, and Diabetes Care, and is co-author of Optimizing Diabetes Care for the Practitioner. Dawn Smiley, MD Associate Professor of Medicine Emory University School of Medicine Atlanta, Georgia Dr Dawn Smiley is an associate professor of medicine at the Emory University School of Medicine in Atlanta, where she also received an MS in clinical research from the university s Graduate School of Arts and Sciences. She currently serves as site director for Grady Memorial Hospital s Endocrinology Fellowship program, working with fellows in inpatient and outpatient settings. Over the past four years, Dr Smiley s main funding has come from the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (NIH-NIDDK) K8 program that supported her research in ketosis-prone diabetes mellitus (KPDM). Her research aims to correlate patient response to treatment with mechanisms and markers of short- and long-term remission and to determine the optimal therapeutic approach to prevent future glycemic decompensation in these patients. With data from the current NIH-NIDDK K8 study and collaborations in the field of epigenetics and insulin signaling mechanisms, Dr Smiley anticipates continued funding that would allow her to validate models for remission in subjects Session 9

3 with KPDM and for subsequent failure after remission; explore the mechanistic link underlying glycemic decompensation, which could potentially be altered (pharmacological activation vs. deactivation of an insulin signaling pathway) to change clinical outcomes; and establish formal treatment guidelines for patients with KPDM. Faculty Financial Disclosure Statements The presenting faculty reported the following: Dr Trence receives grant research support from Eli Lilly and Company and holds stock in sanofi-aventis U.S. LLC. Dr Smiley receives research funding from Abbott Laboratories, sanofi-aventis U.S. LLC, and Merck & Co., Inc.; and served as an advisor to Boehringer-Ingelheim, sanofi-aventis U.S. LLC, and Janssen Pharmaceuticals, Inc. Education Partner Financial Disclosure Statement The content collaborators at Horizon CME have reported the following: Brian Lee, PharmD; Elizabeth Wilkerson, CHES; and Cara Williams, PharmD, have nothing to disclose. Acronym List Acronym Definition ASP insulin aspart BG blood glucose CSII continuous subcutaneous insulin infusion DET insulin detemir FPG fasting plasma glucose GIR glucose infusion rate GLAR insulin glargine GLU insulin glulisine LM lispro mix 75/25 Acronym MDI NPH OHA OGTT PPG SMBG SU T1D T2D Definition multiple daily insulin injections insulin human isophane oral hypoglycemic agent oral glucose tolerance test postprandial glucose self-monitoring blood glucose sulfonylurea type 1 diabetes type 2 diabetes Suggested Reading List Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 28;358(24): ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 28;358(24): American Diabetes Association. Standards of medical care in diabetes 214. Diabetes Care. 214;37(Suppl 1):S14-S8. Arnolds S, Kuglin B, Kapitza C, et al., How pharmacokinetic and pharmacodynamic principles pave the way for optimal basal insulin therapy in type 2 diabetes. Int J Clin Pract. 21;64(1): Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14): Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 29;36(2): Edelman S, Dailey G, Flood T, et al., A practical approach for implementation of a basal-prandial insulin therapy regimen in patients with type 2 diabetes. Osteopath Med Prim Care. 27;1:9. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE comprehensive diabetes management algorithm 213. Endocr Pract. 213;19(2): Hirsch IB. Insulin analogues. N Engl J Med. 25;352(2): Session 9

4 Inzucchi SE, Bergenstal RM, Buse JB, et al., Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 212;35(6): Owens DR, Matfin G, Monnier L. Basal insulin analogues in the management of diabetes mellitus: what progress have we made? Diabetes Metab Res Rev. 214;3(2): Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocri Pract. 29;15(6): UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131): Unger J. Insulin initiation and intensification in patients with T2DM for the primary care physician. Diabetes Metab Syndr Obes. 211;4: Session 9

5 SESSION 9 11am 12:3pm Insulin Therapy in Patients with Type 2 Diabetes: Current and Emerging Basal Insulins SPEAKER Dawn Smiley, MD Dace Trence, MD, FACE Presenter Disclosure Information The following relationships exist related to this presentation: Dawn Smiley, MD, serves on the medical advisory boards for Janssen, Boehringer Ingelheim, and Sanofi. She does contracted research for Abbott Nutrition, Merck and Co., Inc., and Sanofi. Dace Trence, MD, FACE, is a grant recipient of Eli Lilly and stock owner of Sanofi. 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. Disclosure Investigational agents will be discussed during this presentation Insulin Therapy in Patients with Type 2 Diabetes: Current and Emerging Basal Insulins Dawn Smiley, MD Associate Professor of Medicine Emory University School of Medicine Dace Trence, MD, FACE Professor, Division of Metabolism, Endocrinology and Nutrition Director, Diabetes Care Center University of Washington Medical Center Seattle, WA Objectives Outline the benefits of early insulin therapy in patients with type 2 diabetes Discuss when insulin may be initiated for the treatment of patients with type 2 diabetes Describe the advantages and disadvantages of various insulin regimens and apply them in clinical practice for the selection and titration of insulin in patients with type 2 diabetes Identify the barriers to insulin-mediated glucose control and apply strategies to overcome them Describe how improved pharmacokinetic and pharmacodynamic profiles of emerging insulins may reduce hypopglycemia and optimize insulin administration Why have individualized target for glycemic control instead of an A1C <7%? What have the major studies shown us? 1

6 Glycemic Control & Vascular Complications in T2DM Baseline Characteristics of the Landmark Trials in T2DM DCCT/EDIC 1 UKPDS 2,3 ACCORD 4,5 ADVANCE 6 VADT 7 Microvascular Macrovascular Mortality Observational Follow-up Adapted from UK Prospective Diabetes Study (UKPDS33) Group. Lancet. 1998;352: Holman RR, et al. N Engl J Med. 28;359: ACCORD, Gerstein HC, et al. NEJM. 28;358: ACCORD Study Group. NEJM. 21;363: ADVANCE Collaborative Group, Patel A et al. NEJM. 28;358: Duckworth et al, NEJM 29;36: ACCORD 1 ADVANCE 2 VADT 3 UKPDS 4 Number of subjects 1,251 11,14 1,791 4,29 Gender (% males) Age (yrs) Diabetes duration (yrs) Baseline A1C (%) CV events (%) ~35 ~32 ~4 unknown Insulin use (%) ~35 ~1.5 ~5 CV = cardiovascular; T2DM = type 2 diabetes 1. ACCORD, Gerstein HC, et al. NEJM. 28;358: ADVANCE Collaborative Group, Patel A, et al. NEJM. 28;358: Duckworth, et al. NEJM 29;36: Adapted from UKPDS Group. Lancet 1998;352: Risk of CV Events and Death in Patients with Versus without Severe Hypoglycemia (ADVANCE) Study Inclusion Criteria: T2DM + Major Vascular Disease or 1 CV Risk Factor Macrovascular Events 3.45 (2.34, 5.8); p<.1 Lessons Learned from DCCT, UKPDS, ACCORD, ADVANCE Intensive glycemic control generally reduces microvascular risks, but its role in reducing macrovascular risks has been more controversial A1C targets of 6.5%-7.% per se do not increase mortality A1C alone may be a misleading indicator of glycemic control in some patients because rates of protein glycation vary Death Any Cause Death CV Cause 3.3 (2.31, 4.72); p< (2.34, 6.11); p<.1 Severe hypoglycemia can occur even in patients with elevated A1C Severe hypoglycemia rates may increase with increasing A1C Severe hypoglycemia carries definite, serious, and life-threatening risks Death Non-CV Cause 2.86 (1.67, 4.9); p<.1.1 Decreased Risk 1 Increased Risk 1 Adjusted Hazard Ratio (95% CI) Antihyperglycemic agents with the lowest intrinsic risk of hypoglycemia are preferred CV = cardiovascular; CI = confidence interval Zoungas S, et al; ADVANCE Collaborative Group. N Engl J Med. 21;363: Garber, et al. Am J Med. 213;126: Individualizing A1C Targets for Patients with T2DM Most Intensive Less Intensive Least Intensive 6.% 7.% 8.% Psychosocioeconomic Considerations Highly Motivated, Adherent, Knowledgeable, Excellent Self-Care Capacities, & Comprehensive Support Systems Low Moderate Less motivated, Non-adherent, Limited Insight, Poor Self-Care Capacities, & Weak Support Systems Hypoglycemia Risk High Patient Age When should insulin be started in patients with type 2 diabetes? Disease Duration Other Comorbidities 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. 211;154(8):

7 When to Consider Insulin in Type 2 Diabetes When combination oral/injectable agents become inadequate (A1C >6.5% or higher) High FPG or high PPG Unacceptable side effects of other agents Patient with advanced hepatic or renal disease Would earlier insulin initiation be beneficial? Special circumstances (e.g., steroids, infection, pregnancy) Patient with hyperglycemia in the hospital Severely uncontrolled diabetes* FPG = fasting plasma glucose; PPG = postprandial glucose. *Defined as fasting glucose >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 controlled, oral agents can be added and insulin withdrawn if preferred. Nathan DM, et al. Diabetes Care. 29; volume 32, Inzucchi SE, et al. Diabetes Care. 212;35(6): ADA Diabetes Care. 214:37(Suppl 1):S14-S8. Potential benefits of early insulin initiation Diabetes is a progressive disease: resistance to insulin, added to by beta-cell insulin production fall-off 1 Intervention with insulin may be disease-altering, potentially by protecting β-cell function 2,3 Data from several studies support very early insulin initiation 2,3 1. Holman RR. Diabet Res Clin Pract 1998;4(Suppl 1):S21-S Weng J, et al. Lancet. 28;371: Alvarsson M, et al. Rev Diabet Stud. 21;7(3): Insulin in Newly Diagnosed T2DM Percentage of Patients in Remission CSII (N=137) MDI (N=124) OHA (N=121) Treatment was stopped after normoglycaemia was maintained for 2 weeks 51% 45% Days in Remission Target glycemic control was achieved in less time (4 & 5.6 days) and in more CSII and MDI pts (97.1% & 95.2%) than OHA pts (9.3 days and 83.5%) CSII = continuous subcutaneous insulin infusion; MDI = multiple daily insulin injections; OHA = oral hypoglycaemic agents. Weng J, et al. Lancet. 28;371: % p=.12 Insulin in Newly Diagnosed T2DM Cont d Acute Insulin Response (pmol/l per min) CSII in the Remission Group MDI in the Remission Group OHA in the Remission Group Non-Remission Group Before Therapy After Therapy *p<.5 p<.1 P=.6 At 1 Year β-cell function was measured at the end of therapy and 1 year after. Patients treated with continuous insulin therapy had an increase in activity of 16% compared to 15% for those treated with oral agents CSII = continuous subcutaneous insulin infusion; MDI = multiple daily insulin injections; OHA = oral hypoglycaemic agents. Weng J, et al. Lancet. 28;371: C-Peptide Response (mmol/l) Insulin vs SU in Newly Diagnosed T2DM p=.9 SU Baseline * Day 1 Insulin End of Study p=.6 SU = sulfonylurea Alvarsson M, et al. Rev Diabet Stud. 21;7(3): SU ** Day 2 Insulin Newly diagnosed T2DM pts were randomly assigned to glibenclamide (N=26) or 7/3 NPH/R insulin (N=23) 18 pts in SU group and 16 pts in insulin group completed 6 year follow-up Pts on SU more prone to loss of insulin secretion than pts on early insulin treatment. Window of opportunity for beneficial effects of insulin treatment occurs early in the course of diabetes 3

8 T2DM Patients Switched from SU to Preprandial Insulin: Impact on β-cell Function How to Choose Insulin Therapies? β-cell Dysfunction (%) Day 7 Day 14 Glimepiride Day 7 p<.5 Day 14 Insulin Aspart Stage I II IIIa IIIb Active Insulin β-cell Secretion Stage IIIa Stage II Disease Progression Insulin Proinsulin T2DM pts were randomized to continue glimepiride for another 7 days or switch to 8 U of insulin aspart before each meal OGTTs at days 7 and 14 What are the advantages and disadvantages of various insulin regimens? Basal only Basal plus Basal bolus Pre-mixed 5% of the T2DM patients shifted back from stage IIIa β-cell function to early stage II in the preprandial insulin group while β-cell function deteriorated more with glimepiride therapy SU = sulfonylurea; OGTT = oral glucose tolerance test. Pfutzner A, et al. Diabetes Technology & Therapeutics. 26;8: Current Available Human and Analog Insulins Insulin Pharmacodynamics Differ from Insulin Pharmacokinetics Insulin Type Onset Peak, h Duration of Action, h 1 units of insulin aspart administered into the abdomen. Three hours after administration, approximately 4 percent of the insulin or 4 units remain) Rapid-acting Insulin lispro, aspart, glulisine 15 min Short-acting Regular human insulin 3-6 min Intermediate-acting 5 4 Human NPH insulin 1-3 h Long-acting (basal) Insulin glargine 1-2 h No pronounced peak Insulin detemir 1-2 h Relatively flat Up to 24 Hours Edelman S, et al. Osteopath Med Prim Care. 27;1:9. Hirsch IB. NEJM 25;352(2): Accessed March 24, 214. Hirsch I. N Engl J Med. 25;352: Insulin Remaining (%) Premixed (Biphasic) Insulin Analogs Premixed insulins Humalog 75/25, 5/5 Intermediate + rapidacting Novolog 7/3 Intermediate + rapid-acting Humulin 7/3 Intermediate + short-acting Novolin 7/3 Intermediate + short-acting Comparative InsulinTrials in T2DM Summary of Key Findings Any insulin will lower glucose and A1C All insulins are associated with some weight gain and some risk of hypoglycemia The larger the doses and the more aggressive the titration, the lower the A1C, but often with a greater possibility of adverse effects Long-acting insulin analogs reduce the incidence of overnight hypoglycemia Rapid-acting insulin analogs reduce postprandial glucose excursions (compared with corresponding human insulins [NPH, Regular]), but they generally do not result in clinically significantly lower A1C Inzucchi SE, et al. Diabetologia. 212;55:

9 Sequential Insulin Strategies in T2DM Basal insulin + 1 (meal-time) rapid-acting insulin injection Basal insulin + 2 (meal-time) rapid-acting insulin injection Non-insulin regimens Basal insulin only (usually with oral agents) Premixed insulin twice daily Flexibility more flexible less flexible Adapted from Inzucchi SE, et al. Diabetes Care. 212;35: Number of injections Regimen complexity 1 low 2 mod. 3+ high Adding Insulin to OADs Improves Glycemic Control (Results of Large RCTs) Study Treatment Baseline A1C Resulting A1C STEPWISE (211) DET + -3 ASP* weeks 1 DET + -3 ASP weeks 2 BIASP BID a b 4-T (27) ASP TIDa b DET QD a weeks 3 GLAR QD + GLU QD d Riddle et al. (211) GLAR QD + -3 GLU c BIASP BID DURABLE (211) LM 75/25 BID weeks 4 GLAR QD Davidson et al. (211) 14 weeks 5 GLAR QD * Measured PPG; Estimated meal size; a A second type of insulin could be added beginning at 24 weeks if HbA1C 8.% on 2 consecutive readings or > 1%; b p<.1 vs DET QD; c p<.5 vs BIASP; d p<.25 vs BIASP. 1. Meneghini L, et al. Endocr Pract. 211;17: Holman RR, et al. N Engl J Med. 27;357: Riddle MC, et al. Diabetologia. 211;54(suppl 1):S1-S Buse JB, et al. Diabetes Care. 211;34: Davidson MB, et al. Endocr Pract. 211;17: Strategies for Insulin Selection 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 1 NPH a little more hypoglycemic risk than analogs 2 Cost NPH $ Analogs $$-$$$ Insurance coverage Analogs coverage varies and may require prior authorization 1. ORIGIN Trial Investigators. N Engl J Med. 212;367(4): Riddle M et al. Diabetes Care 23; 26: Advantages Basal only Insulin Regimens Convenient, 1 shot only, low risk of hypoglycemia especially with analogue insulin Appropriate for most patients starting insulin Basal plus Two injections only, bolus typically targeted to largest meal of day Appropriate for patients not achieving goal A1C on basal insulin and wanting only two shots daily Disadvantages Basal only Does not address PPG, may not provide sufficient insulin in advance disease Basal plus May not cover all prandial needs Plank J, et al. Arch Intern Med. 25;165: Horvath K, et al. Cochrane Database Syst Rev. 27;(2):CD5163. Davies M, et al. Diabetes Care. 25;28: Yki-Ja rvinen H, et al. Diabetes Care. 27;3: Crasto W, et al. Postgrad Med J. 29;85: Insulin Regimens Cont d Insulin Regimens Cont d Advantages Basal bolus Disadvantages Basal bolus Advantages Pre-mixed Disadvantages Pre-mixed Flexible regimen, basal plus bolus whenever eating meal, allows for correction insulin use Appropriate for patients willing to do multiple injections daily with frequent BG monitoring and capable of managing the complexity Many injections, adds complexity to daily insulin regimen Can minimize daily injection number Appropriate for patients that cannot use basal bolus, wanting only 2 injections, and who have regular lifestyles, eat similar amounts at similar times each day (similar total calories and similar content for carbohydrate/fat/protein) Fixed ratio, does not allow flexibility in dosing, increased risk of hypoglycemia Plank J, et al. Arch Intern Med. 25;165: Horvath K, et al. Cochrane Database Syst Rev. 27;(2):CD5163. Davies M, et al. Diabetes Care. 25;28: Yki-Ja rvinen H, et al. Diabetes Care. 27;3: Crasto W, et al. Postgrad Med J. 29;85: Plank J, et al. Arch Intern Med. 25;165: Horvath K, et al. Cochrane Database Syst Rev. 27;(2):CD5163. Davies M, et al. Diabetes Care. 25;28: Yki-Ja rvinen H, et al. Diabetes Care. 27;3: Crasto W, et al. Postgrad Med J. 29;85:

10 A Recommendation for Starting and Adjusting Basal Insulin Bedtime or morning long-acting insulin OR Bedtime intermediate-acting insulin Daily dose: 1 units or.2 units/kg How do you start and titrate insulin? 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. Continue regimen and check A1C every 3 months Data from Nathan DM, et al. Diabetes Care. 29;32: When Basal Alone is Not Enough 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 BG = blood glucose. How to Intensify Using the Basal Plus Approach 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 2nd prandial dose Usually need about 8-12 units of prandial insulin to cover meal(s) HS = at bedtime; PPG = postprandial glucose. Lankisch, et al. Diabetes, Obesity and Metabolism. 28:1; Meneghini, et al. Endocrine Practice. 211;17; Premixed vs Basal Insulin Analogs in T2DM A1C (%) * A1C<7% 5 66% 4% P <.1 Hypoglycemia 4 (events/yr) P <.5 Baseline Wk 28 Baseline Wk 28 Weight (kg) BID Bisphasic 5.4 QD Insulin3.5 P <.1 Insulin Aspart 7/3 Glargine Insulin dose (units/day) 79±4 51±27 P <.5 N=117 N=116 * P <.1 vs glargine. Data from Raskin P, et al. Diabetes Care. 25;28: Premixed Basal P-value Risk of Hypoglycemia Increases as Therapy Intensifies Percentage of Patients Reporting 1 Hypoglycaemic Event per Year For all therapies, the significance of differences between levels is p<.1.8% Diet Alone 1.7% 7.9% SU = sulfonylurea Wright AD, et al. J Diabetes Complicat. 26;2: (UKPDS 73). 21.2% Metformin SU Basal Insulin Only 32.6% Basal + Bolus Insulin 6

11 Patient Willingness to Start Insulin Insulin is the most effective therapy we have at reducing glucose, so why are there not more diabetes patients using it to achieve glycemic goals? Patients (%) Willingness to Start Insulin/Psychological Insulin Resistance 17.2 Unwilling 34.7 Ambivalent 48.1 Willing N=14 insulin-naïve Type 2 diabetes subjects. Polonsky WH, et al. Curr Med Res Opin. 211;27(6): Factors Related to Psychological Insulin Resistance among Ambivalent or Unwilling Patients More negative and fewer positive beliefs about starting insulin More negative feelings about their current medications More diabetes-related distress Physician Barriers to Starting Insulin Therapy Pain associated with injections 48.4 Pain associated with testing Hypoglycemia Clinical Inertia Failure of health care providers to initiate or intensify therapy when indicated Patient compliance Percent (%) of Primary Care Physicians Nakar S, et al. J Diabetes Complications. 27;21(4): Identify Patient Barriers Patient Barriers to Insulin Initiation Ask patient, listen to response, and confirm answer What is the hardest thing about taking care of your diabetes? What concerns or worries do you have about using insulin to treat your diabetes? Barriers Sense of failure Insulin causes complications Loss of independence Insulin ineffectiveness Addressing the Barriers Insulin is a physiologic, inevitable step Discuss the eventual use of insulin with patients early Do not use insulin as threat, but as solution Acknowledge the patient s fear Provide information about the provider s experiences of the effectiveness and safety of insulin Empower patient to take control of BG Provide self-management education Use insulin pens and insulin regimens that offer maximum flexibility Give limited trial with appropriate insulin doses Monitor for symptom improvement Patient to monitor for improved glucose at time of primary insulin effect (e.g. AM for basal insulin) Adapted from Funnell MM. Clinical Diabetes. 27;25(1):

12 Patient Barriers to Insulin Initiation Physician Barriers to Insulin Initiation Barriers Addressing the Barriers Barriers Addressing the Barriers Fear of injections Fear of hypoglycemia Weight gain Cost Insulin needles are very small Less painful than finger sticks for BG testing Have patient give a saline injection in office Insulin pen is usually less intimidating Educate: with basal insulin the incidence is low, especially with analog insulin Teach patient to recognize and treat (Rule of 15) Initially increase glucose monitoring to reassure Meet with dietitian before initiation of insulin Mention options of combinations with metformin and GLP- 1 receptor agonists Basal Insulin is usually less expensive than adding multiple other non-generic medications Adapted from Funnell MM. Clinical Diabetes. 27;25(1): Clinical inertia Suboptimal insulin knowledge Fear of hypoglycemia Use systems to facilitate chronic disease care EMR reminders to support real-time treatment and monitor results Education on insulin selection, initiation, and titration Incidence is low, especially with basal analogs Experience reassures Review glucose log to identify patterns of hypoglycemia Have patient meet with dietitian before initiation of insulin More physiologic insulin delivery may minimize weight Weight gain gain Minimize with metformin and GLP-1 receptor agonists GLP-1 = glucagon-like peptide-1. Adapted from Funnell MM. Clinical Diabetes. 27;25(1): Derr RL, et al. Diabetes Spectrum. 27; 2(3): Insulin Non-Adherence Theoretically the potential for insulin to lower glucose is limitless, so why is it that not all diabetes patients initiated on insulin therapy are achieving their glycemic goals? Common problem 1,2 More than 1 in 3 patients do not adhere to their insulin regimen In insulin-naïve patients, 4.5% do not fill their insulin prescription and 25.5% do not continue their insulin Primary reasons for non-adherence 2 Lack of organization in daily life and prioritization of insulin treatment Lack of patient engagement Plans to improve lifestyle in lieu of starting insulin Loss of independence (negative impact on social and work life) Fear of injection Hypoglycemia Complexity of some insulin regimens 1. Accessed March 6, Karter AJ, et al. Diabetes Care. 21;33(4): Patient Reported Reasons for Missing Insulin Injections Dread taking injections Insulin injections negatively affect activities Injections interfere with eating or exercise Often worry about hypoglycemia Need to plan daily activities around injections Grunberger G. Diabet Obes Metab. 213;15(suppl 1): Years of US Survey Some Key Factors In Patient Engagement Patient Education Is a Key Intrinsic Factors Attitudes & health beliefs Depression Self-efficacy Level of diabetes knowledge Technical skill Ethnic perspective Functional health literacy Adapted from Rodriguez KM. Clin Therapeutics. 213;35(2): Extrinsic Factors Financial capabilities Family influence Workplace environment Clinical relationships Access to care 8

13 Gaps in Diabetes Education Persist Failure to Escalate Insulin Therapy % Attending Diabetes Education Class Fear of hypoglycemia Weight gain Regimen too complex for patient Patient non-adherence Years of US Survey Ali MK, et al. NEJM. 213;368(17): Physicians Beliefs Regarding Insulin Therapy Primary Care Specialist I wish there was an insulin treatment that would cover patients in case they forgot a dose* 9 85 p<.5 I believe that I must manage safety and efficacy but it is difficult to optimally manage both with insulin I would treat my patients more aggressively if there was no concern about hypoglycemia* p<.5 79 What are the differences among currently available basal insulins? A significant number of patients do not have adequate blood glucose levels with insulin treatment* 85 9 p<.5 Peyrot M, et al. Diabetic Medicine. 212;29: Percentage (%) Current Available Basal Insulins Human basal insulin NPH insulin Analog basal insulin Insulin glargine Insulin detemir Relative Intra-individual Variations with Basal Insulins Onset of Action* (hours) End of Action* (hours) Duration of Action* (hours) GIR T max (time of peak) Within-Subject Variability* (CV% of AUC-GIR) NPH Glargine Detemir Data presented here are from studies in subjects with type 1 diabetes. GIR = glucose infusion rate; AUC-GIR = area under the GIR curve; NR = not reported; PK/PD = pharmacokinetic and pharmacodynamic; PG = plasma glucose; CV = coefficient of variation. * The definition may vary among studies. Additionally, specific clamp conditions such as the target PG (iso- or euglycaemic) may influence these PD parameters. Within-subject variability (day-to-day variability) is expressed as the coefficient of variation of the AUC- GIR study period from clamp studies where each subject received the same insulin dose in repeated occasions. Rossetti, et al. Diabetes Obesity Metab [Epub ahead of print; published online 9 Feb 214] 9

14 GIR (mg/kg/min) Pharmacodynamics of Available Basal Insulin Analogs Glargine Detemir.3 U/kg T1D.35 U/kg T1D U/kg T1D 4..4 U/kg T1D.4 U/kg T1D.4 U/kg T2D U/kg T2D U/kg T2D 3..8 U/kg T2D Time (hours) Time (hours) Glucose Infusion Rates (GIR) after Basal Insulin Injection T1D = type 1 diabetes; T2D = type 2 diabetes. Garber AJ Diabetes Obesity Metab; [Epub ahead of print; published online 31 Oct 213] GIR (mg/kg/min) Glargine vs NPH in Treat-To-Target No Difference in A1C but Reduced Hypoglycemia A1c Level (%) Glargine NPH 12 Treatment Duration (weeks) Adapted from Riddle M, et al. Diabetes Care. 23;26: Cumulative Number of Events Documented Glucose 56 mg/dl mmol/l) NPH Glargine Hypoglycemia Reduced 42-46% Time (days) Hypoglycemia Reduced with Basal Insulins Reducing Risk of Hypoglycemia in Pursuit of A1C Goals Hypoglycemia (events pt-yr -1 ) A1C (%) Glargine NPH Hypoglycemia (events pt-yr -1 ) A1C (%) NPH Detemir Characteristics of Available Basal Insulin Analogs Benefits over NPH Longer duration of action Less variability Less weight gain Less hypoglycemia Room for Improvement More consistent 24+ hour coverage Flat time-action profile Less day-to-day variability Less weight gain Less hypoglycemia More suppression of hepatic glucose production Little S, et al. Diabetes Technol Ther. 211:13(suppl 1):S53-S64. Simon ACR. Diabetes Technol Ther. 211;13(suppl 1):S Grunberger G. Diab Obes Metab. 213; 15(suppl 1):1-5. Differences in Basal Analog Insulins Randomized Trial of Glargine QD vs Detemir BID Glargine QD is non-inferior to Detemir BID in reducing A1c and hypoglycemia Detemir dose was significantly higher in this study Detemir caused less weight gain, difference of -.77 kg (p<.1) A1C Level (%) 9. Glargine (N=478) 8.5 Detemir (N=486) Daily Insulin Dose (units/kg) p< Treatment Duration (weeks) Treatment Duration (weeks) What is different about basal insulins in development that may help improve insulin therapy? Swinnen SG, et al. Diabetes Care. 21;33:

15 Characteristics of the Ideal Basal Insulin PD profile should be flat (peakless) Low risk of hypoglycemia Duration of action of 24 hours Low variability within individual patients Arnolds S, et al. Int J Clin Pract. 21;64(1): Basal Insulins in Development High concentration glargine (U3)* U3 insulin glargine offers a smaller depot surface area leading to a reduce rate of absorption Provides a flatter and prolonged pharmacokinetic and pharmacodynamic profiles and more consistency Half-life is ~23 hours Steady state in 4 days Duration of action 36 hours *Not FDA approved Garber AJ. Diabetes Obesity Metab; [Epub ahead of print; published online 31 Oct 213]. Owens DR, et al. Diabetes Metab Res Rev. 214;3(2): Steinstraesser A, et al. Diabetes Obes Metab. 214 Feb 26. [Epub ahead of print]. Accessed March 11, 214. Basal Insulins in Development Cont d PEGylated Insulin Lispro* Polyethylene glycol polymer covalently attached to lispro Half-life 2-3 days Steady state in 7-1 days Duration of action >36 hours Basal Insulins in Development Cont d Insulin degludec* desb3 insulin acylated (16 carbon fatty acid chain) at LysB29 Duration of action >42 hours Half-life ~25 hours Detectable for at least 5 days Steady state in 2-3 days FDA denied approval in 213, research continues *Not FDA approved Garber AJ. Diabetes Obesity Metab; [Epub ahead of print; published online 31 Oct 213]. Owens DR, et al. Diabetes Metab Res Rev. 214;3(2): Accessed March 11, 214. Sinha VP, et al. Diabetes Obesity Metab. 214;16(4): *Not FDA approved Garber AJ. Diabetes Obesity Metab; [Epub ahead of print; published online 31 Oct 213]. Owens DR, et al. Diabetes Metab Res Rev. 214;3(2): Pharmacodynamics of U3 Glargine vs U1 Glargine U1 Glargine vs U3 Glargine in Type 2 Diabetes GIR (mg/kg -1 min -1 )* SC Injection U1.4 U/kg -1 U3.4 U/kg Time (hours) U3.6 U/kg -1 U3.9 U/kg -1 Mean A1C (%) U3 U1 Mean change in A1C for both treatment groups -.83% 6.5 Baseline Week 12 Time Month 6 Month 6 LOCF No difference in A1C change The U-3 glargine has a flatter more prolonged effect The time it takes for 5% of the effect of a single injection U-1 = 12.1 hours U-3 = 16.7 hours GIR = glucose infusion rate. Tillner J, et al. Poster 92P 73 rd ADA Scientific Sessions June 21-25, 213, Chicago, IL. Accessed March 21, 214. Lower rate of severe or confirmed hypoglycemia, particularly overnight Time period U1 U3 RR with U3 CI -6 months Nocturnal 57.5% 44.6% weeks 6 mo Nocturnal 46.% 36.1% months 24 hours 87.8% 81.9% Riddle MC et al. Presentation 43-LB 73 rd ADA Scientific Sessions June 21-25, 213, Chicago, IL. Accessed March 21,

16 U1 Glargine vs. U3 Glargine in Type 2 Diabetes Patients on OADs Pharmacodynamics of Degludec Randomized, multicenter, open-label, 6-month study with 811 patients No difference in the change in A1C from baseline between U1 vs. U3 Percentage of patients with severe or nocturnal hypoglycemia from 3 to 6 months was significantly lower with U3 vs U1, 21.6% vs. 27,9% (RR.77, p=.38) Glucose Lowering Effect on Day 6 (mg/kg/min) Ideg.8 U/kg 6 Ideg.6 U/kg Ideg.4 U/kg Time since Injection (hours) OADs = oral antihyperglycemic drugs; RR = relative risk. Yki-Järvinen H, et al. IDF World Diabetes Congress December 2-6, 213, Melbourne, AU. Accessed March 21, 214. Josse RG and Woo V. Diabetes Obes Metab. 213;15(12): Degludec vs Glargine In Type 2 DM Equal Efficacy, Less Nocturnal Hypoglycemia with Degludec but no difference in severe hypoglycemia A1C (%) Cumulative Events per Participant Time (weeks) Time (weeks) Garber AJ, et al. Lancet. 212;379(9285): Cumulative Events per Participant A1C (mmol/mol) Insulin Degludec once-daily (N=744) Insulin Glargine once-daily (N=248) Time (weeks) 52 Pharmacodynamics of PEGylated Insulin Lispro (LY265541) After First Dose and 14th Dose GIR (mg/kg/min) DAY 1 Glucose Infusion Rate 3. nmol/kg (.33 U/kg) 4.5 nmol/kg (.5 U/kg) 6. nmol/kg (.67 U/kg) 9. nmol/kg (1. U/kg) GIR (mg/kg/min) Time (hours) GIR = glucose infusion rate. Sinha VP, et al. Diabetes Obesity Metab. 214;16(4): DAY 14 Glucose Infusion Rate 3. nmol/kg (.33 U/kg) 4.5 nmol/kg (.5 U/kg) 6. nmol/kg (.67 U/kg) 9. nmol/kg (1. U/kg) Time (hours) PEGylated Insulin Lispro (LY265541) vs Glargine A1C (%) Weight (kg) Treatment Period Week Treatment Period 2 Rosenstock J, et al. Diabetes Care. 213;36(3): In Type 1 Diabetes Mellitus Reduced nocturnal hypoglycemia Increased overall hypoglycemia Weight sparing Reduced fasting glucose variability Reduced prandial insulin Glargine LY Patients (%) Weight Differences between Basal Insulin Glargine vs LY p= Any Weight Loss T2DM p= Any Weight Loss T1DM Jacober SJ, et al. Diabetes Obesity Metab. 214;16(4): p= % Weight Loss T2DM Insulin Glargine LY p= % Weight Loss T1DM 12

17 Basal Insulins Current available analog basal insulin products have some benefit over human basal insulin Glargine has the longest duration of action of current available basal insulins The basal insulin products in development have longer duration of action and flatter pharmacokinetic profiles. Potential advantages include: Further reduction in hypoglycemia rates Weight loss (PEGylated lispro) Single injection for high doses (U3 glargine) Questions Submitted by Attendees Online Question 1 Please address the challenges of basal insulin for home bound elderly who may be dependent on a daily nurse visit for insulin - review management guidelines Question 2 At what dose do you split the long acting insulin to control glucose in type 2 dm? Question 3 Any role for continuing 7/3? Should all orals be discontinued when insulin is initiated? Question 4 Do you have any medical magic on handling the insulin spiral which is insulin stimulates hunger more intake raises blood glucose and then requires more insulin and then increases weight then more insulin. Most any time I introduce insulin in hte type 2 patient they gain weight and we spiral upward 13

18 Question 5 What oral medications should be used with Insulin to treat type 2 DM? the best combination? Question 6 How do you minimize weight gain in treatment of type 2 dm? started on metformin. must minimize cost as has no prescription coverage Question 7 A1C goals in ever-growing elderly population including frail elderly Question 8 My patient has very poor controlled DM. When I increased Insulin, pt had hypoglycemia, even though increased very little. When I reduced Insulin dose, blood sugar became high. Endo consulted and Insulin dose was changed by very good endocrinologist, but still poor controlled. What should I do? Questions? 14