Individualizing Therapy int2dm With Insulin

Transcription

1 Individualizing Therapy int2dm With Insulin Etie Moghissi, MD, FACP, FACE Clinical Associate Professor University of California, Los Angeles Los Angeles, California

2 OBJECTIVES: At the conclusion of this activity, participants should be able to: Compare the pharmacodynamic and therapeutic characteristics of ultralong-acting basal insulins with those of previously approved insulins Calculate appropriate doses of ultralong-acting basal insulin for patients with and without prior insulin treatment Identify simplified, patient-centered treatment regimens incorporating ultralong-acting insulin for advancing therapy in patients with T2DM

3 T2DM Is a Progressive Disease Glucose, mg/dl Prediabetes (obesity, IFG, IGT) Diabetes diagnosis Postmeal glucose Fasting glucose Relative Amount β-cell failure Insulin resistance Insulin level T2DM onset Years Disease progression occurs no matter how well patients self-manage: insulin therapy should not be used as a threat or described as failure Kendall DM, et al. Am J Med. 2009;122(6 suppl):s37-s50; Kendall DM, et al. Am J Manag Care. 2001;7(suppl):S327-S343; DeFronzo RA. Diabetes. 2009;58: ; Inzucchi SE, et al. Diabetes Care. 2015;38: ; American Diabetes Association. Diabetes Care. 2016;39(suppl 1):S1-S112.

4 Insulin Is the Universal Agent for Achieving Glycemic Control At diagnosis 1 In combination with non-insulin agents 2-5 In long-duration disease 3,6 Benefit especially likely in: Treatment-naive individuals with hyperglycemic symptoms and A1C > 9% Latent autoimmune diabetes in adults (LADA) Individuals with hyperlipidemia and/or hypertension Recommended for use in combination with most other major classes of antihyperglycemic agents Combinations reduce glycemic variability compared with insulin-only regimens Loss of β-cell function is inevitable as T2DM progresses With appropriate dose adjustment, insulin can be used in any patient (including those with comorbidities that preclude the use of other agents) 1. Owens DR. Diabetes Technol Ther. 2013;15: ; 2. Drugs@FDA. Accessed October 11, 2015; 3. American Diabetes Association. Diabetes Care. 2016;39(suppl 1):S1-S112; 4. Garber AJ, et al. Endocr Pract. 2016;22:84-113; 5. Hirsch IB, et al. Diabetes. 2015;64(suppl 1):A100 [abstract 385-OR]; 6. Lebovitz HE. Diabetes Rev. 1999;7:

5 Benefits and Limitations of Early Initiation of Insulin Therapy vs Conventional Care Benefit: Rapid normalization of blood glucose levels Benefit: Reduces risk of progression from prediabetes to T2DM Benefit: Consistently better long-term glycemic control Benefit: Reduces risk of microvascular complications if A1C > 6.4% Benefit: No increased CVD risk Limitation: Increased risk of severe hypoglycemia Hanefeld M, et al. Diabetes Ther Feb 10. [Epub ahead of print]/

6 Current Options Among Insulin Products Type Basal Insulins Prandial Insulins Premixed Insulins Human 1 U-100 NPH U-100 regular human insulin (RHI) U-500 RHI Technosphere inhaled insulin U /30 RHI Analogue 1 U-100 glargine U-100 glargine equivalent a U-100 detemir U-100 degludec U-200 degludec U-300 glargine U-100 lispro U-100 aspart U-100 glulisine U-200 lispro U /50 lispro U /30 aspart U /25 lispro U /30 degludec/aspart All recently approved insulins are only available in pens 1,e; red text denotes which insulins are only available in prefilled pens Analogue insulins are associated with less hypoglycemia than human insulins, although these differences are not always statistically significant 2 a In the US, U-100 glargine equivalent is not approved as a biosimilar product Drugs@FDA. Accessed January 8, 2016; 2. Singh SR, et al. CMAJ. 2009;180:

7 New slide Insulins Are Available in 4 Different Concentrations Concentrations and Number of Units per Container 1 Concentration Units/mL Units/Vial Units/Pen U a 300 b U Not available in vials U Not available in vials 600 b 450 c U ,000 d 1500 c Insulin pens significantly reduce the risk of dosing errors and hypoglycemic events 2 Pens completely eliminate the need for converting doses based on the volume of insulin injected Dosing errors with U-500 insulin vials are especially dangerous, but pens are now available 3,e a 10 units/vial; b 3 ml/pen; c 1.5 ml/pen; d 20 units/vial; e given the potential for a 5-fold higher insulin dose relative to the same volume of a U-100 insulin. 1. Drugs@FDA Newton C, et al. AACE Annual Meeting [abstract 271]. 3. Segal AR, et al. Am J Health Syst Pharm. 2010;67:

8 Comparing the Therapeutic Characteristics of Older and Newer Basal Insulins

9 Pharmacodynamic Profile of a Hypothetical Ideal Basal Insulin 400 Glucose, mg/dl Time 06:00 10:00 14:00 18:00 22:00 02:00 06:00 An ideal basal insulin would yield a flat glucose profile throughout the day, on different days, and in different people 1,2 1. Zinman B. N Engl J Med. 1989;321: Garber AJ. Diabetes Obes Metab. 2014;16:

10 Ultralong-Acting Basal Insulins Have Minimal Glycemic Variability GIR, mg/kg/min U-300 glargine 1,a Average glucose infusion rate (GIR) Time, h Period 1 Period 2 GIR, μmol/kg/min Older Basals 3,b NPH Detemir Glargine Blood Glucose Level, mmol/l U-100 degludec 2 a 2-period crossover study in T1DM; n = 50. b 3-period crossover study in T2DM. Individual patient profiles Mean profile Time Since Injection, h Time, h 1. Becker RH, et al. Diabetes Obes Metab. 2015;17: Haahr H, Heise T. Clin Pharmacokinet. 2014;53: Porcellati F, et al. Diabetes Care. 2011;34:

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18 Trial Design SWITCH Reduce pre-trial insulin dose (basal and bolus) by 20% at V2 Reduce Treatment period A insulin dose (basal and bolus) by 20% at V34 T1DM patients currently on NPH or IDet OD or BID plus bolus IDeg once daily + IAsp 2-4 times daily IDeg once daily + IAsp 2-4 times daily IGlar once daily + IAsp 2-4 times daily IGlar once daily + IAsp 2-4 times daily Discontinue at V2 Treatment period A Treatment period B V1 V2 V34 V66 V67 Screening (0-2 weeks) switch Randomisation 1:1 16 weeks 16 weeks washout periodmaintenance period Crossover 16 weeks washout period 16 weeks maintenance period Follow-up (at least 1 week) 18

19 Results: Switch 1 Hypos during the maintenance period per 100 patient years Severe OR Severe OR % Sever e Rate of BG +Sx Conf BG Noc conf Severe Degludec Glargine Stats SS SS SS SS RRR 11% 36% 35%

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21 Efficacy and Safety of U-100 Glargine Equivalent (LY ) vs U-100 Glargine in Insulin-naive Patients With T2DM a Overall Hypoglycemia b Nocturnal Hypoglycemia c Severe Hypoglycemia d P = NS P = NS P = NS Equivalent change in A1C ( 1.48% vs 1.54%, LY vs GLAR, P = NS) Equivalent insulin dose (0.42 vs 0.44 U/kg, LY vs GLAR, P = NS) Equivalent weight gain (2.0 vs 2.2 kg, LY vs GLAR, P = NS) a n = 221 (LY), n = 236 (GLAR), mean age = 58 y, duration of diabetes = 11 y, BL A1C = %, BL wt = kg, BL BMI = 32 kg/m 2 ; b plasma glucose 70 mg/dl or sign or symptom of hypoglycemia; c between bedtime and waking; d requiring assistance, baseline to month 6. Rosenstock J, et al. Diabetes Obes Metab. 2015;17:

22 Summary U-100 Glargine Equivalent 100 units/ml Biologically equivalent to U- 100 glargine Compared with U-100 glargine: Equally effective Equivalent hypoglycemia Equivalent weight gain U-300 Glargine 300 units/ml Same molecule as U-100 glargine but more concentrated Compared with U-100 glargine: Equally effective Less hypoglycemia a Equivalent weight gain U-100 and U-200 Degludec 100 or 200 units/ml Novel molecular configuration Compared with U-100 glargine a : Equally effective Less hypoglycemia b Equivalent weight gain U-100 glargine equivalent has the same therapeutic characteristics as U-100 glargine Ultralong-acting basal insulins have a flatter time-action profile, with less glycemic variability, and may be less likely to cause hypoglycemia than first-generation insulin analogues a Significantly less overall hypoglycemia in insulin-naive patients. b Significantly less nocturnal hypoglycemia in insulin-naive patients.

23 Meet Maria History & Vital Signs Woman, white 56 years old T2DM for 6 years Height: 5 ft 1 in Weight: 152 lb BMI: 28.7 kg/m 2 BP: 138/80 mm Hg Heart rate: 112 beats/minute (bpm) Current Medications Glycemic control Metformin XR: 2000 mg/d Glimepiride: 4 mg/d Other medications ACE inhibitor Statin Laboratory Results Fasting plasma glucose (FPG): 178 mg/dl A1C: 9.1% Lipids: Within normal limits (WNL) egfr: 72 ml/min/1.73 m 2 Liver function tests (LFTs): WNL Increasing A1C over past 2 years, despite increased dose of sulfonylurea Admits to missing her medication 1 day per week due to irregular schedule and work-related travel Has had minor hypoglycemia with glimepiride and would like to avoid going through that again Is hesitant but willing to consider adding insulin to her regimen if necessary

24 Initiating and Titrating Newer Ultralong- Acting Basal Insulins

25 Guideline Recommendations for Initiating and Titrating Basal Insulin in Patients With T2DM Initial dose Titration ADA/EASD Guidelines 10 U/d or U/kg 10%-15% or 2-4 U once or twice weekly to fasting blood glucose (FBG) of mg/dl Hypoglycemia: determine and address cause; reduce dose by the greater of 4 U or 10%-20% Once-daily basal insulin, with injection timing based on patient s schedule and glucose profile, is a convenient way to initiate insulin American Diabetes Association. Diabetes Care. 2016;39(suppl 1):S1-S112.

26 Guidance for Initiating and Titrating Newer Basal Insulins: U-100 or U-200 Degludec 1 Starting Dose of U-100 or U-200 Degludec in Insulin-Naive Patients 10 U, once daily Starting Dose of U-100 or U-200 Degludec in Patients Switching From Another Basal Insulin U-100 glargine U-100 detemir U-100 NPH Same dose 1 ; consider 20% dose reduction if switching from twice-daily basal insulin dosing 2 U-100 degludec Same dose for U-100 and U-200 U-300 glargine Injection time Titration step Not specified (but 20% reduction may be prudent) Once daily, any time ( 8 h since last dose) Calculate average FPG from the preceding 2 days, compare with goal: Uptitrate by 2 U if above goal Maintain dose if at goal Downtitrate by 2 U if below goal Max. titration frequency Dwell time 3-4 days, 1 but no more than weekly may be better 2 6 seconds 1. Drugs@FDA. Scripts/cder/DrugsatFDA. Accessed January 8, Vora J, et al. Diabetes Res Clin Pract. 2015;109:19-31.

27 Insulin Pens Can Improve Outcomes and Are Associated With Lower Risks of Dosing Errors and Hypoglycemia Than Vial-and-Syringe Insulin Human insulins are generally administered with a vial and syringe Analogue insulins are generally administered with a pen Patient copayments for pens may be the same as for vials Use the shortest possible needles ( 8 mm) After injecting, keep the needle in the skin for the recommended dwell time Rotate sites to avoid lipohypertrophy Perez-Nieves M, et al. Curr Med Res Opin. 2015;31: ; Molife C, et al. Diabetes Technol Ther. 2009;11: ; Aetna Aetna Pharmacy Plan Drug List. Accessed January 27, 2016; Becton Dickinson Diabetes. Step by step injection guide. Accessed January 27, 2016; Frid A, et al. Diabetes Metab. 2010;36(suppl 1):S3-S18; Drugs@FDA. Accessed January 8, 2016.

28 Meet Joe History & Vital Signs Man, black 67 years old T2DM, 12 years Myocardial infarction, 11 years ago Height: 5 ft 9 in Weight: 217 lb BMI: 32 kg/m 2 BP: 144/80 mm Hg Heart rate: 78 bpm Current Medications Glycemic control Metformin XR: 2000 mg/d Sitagliptin: 100 mg/d U-100 glargine: 80 U/d, AM injection Other medications ARB and HCTZ Statin Aspirin Laboratory Results FPG: 175 mg/dl SMBG: mg/dl A1C: 8.5% Lipids: WNL egfr: 62 ml/min/1.73 m 2 LFTs ALT: 65 U/mL AST: 42 U/mL Recognizes that his FPG is not where it should be but doesn t want to increase his insulin dose because the injection volume is already uncomfortably large Does not want to split the insulin to AM and PM doses because he s a musician and is often busy in the evening, playing with his band

29 Simplifying Intensification of Basal Insulin Therapy in T2DM

30 Overview of Therapeutic Characteristics of New and Emerging Prandial Insulins U-200 lispro (approved) 1,2 Inhaled insulin (approved) 2,3 Faster-acting aspart (submitted) 4,5 Bioequivalent to U-100 lispro 1 Time-action characteristics similar to U-100 lispro 1,2 Prefilled pen injector 2 Concentration permits smaller injection volume 2 Much faster and shorter acting than subcutaneous (SC) insulins (variable bioavailability, inconsistent dosing effect) 2 Not as effective as SC but less weight gain 3 Significantly less severe hypoglycemia 3 Limit use to nonsmokers without pulmonary disease 2,3 Greater glucose-lowering effect within 90 minutes after dosing vs currently available aspart 4,a Significantly lower PPG for faster-acting aspart vs currently available aspart 5,b a Randomized, 3-way crossover study in 52 adults with T1DM. b Randomized trial in 43 adults with T1DM treated with continuous subcutaneous insulin infusion. 1. de la Peña A, et al. Clin Pharmacol Drug Dev. 2016;5: Drugs@FDA. Scripts/cder/DrugsatFDA. Accessed January 8, Pittas AG, et al. Lancet Diabetes Endocrinol. 2015;3: Heise T, et al. Diabetes Obes Metab. 2015;17: Bode B, et al. Diabetes. 2015;64(suppl 1):A253 [abstract 994-P].

31 Treatment Algorithms for Advancing Beyond Basal Insulin Therapy Have Been Updated ADA/EASD: consider a trial of a GLP-1 receptor agonist 1 AACE/ACE: consider a GLP-1 receptor agonist, an SGLT2 inhibitor, or a DPP-4 inhibitor 2 Approval Status for Use of GLP-1 receptor agonists in Combination With Insulin Agent Basal Prandia l Albiglutide mg QW 3 Dulaglutide mg QW 3 Exenatide 5-10 μg BID 3 Exenatide 2 mg QW 3 Liraglutide mg QD 3 Lixisenatide (NDA accepted by US FDA) 4 X X X See note 5,6 X Not Recommended X Note: Has been tested in combination with insulin glargine. 5,6 1. American Diabetes Association. Diabetes Care. 2016;39(suppl 1):S1-S112; 2. Garber AJ, et al. Endocr Pract. 2016;22:84-113; 3. Drugs@FDA. Accessed January 27, 2016; 4. Sanofi. Review-by-FDA. Accessed January 27, 2016; 5. Riddle MC, et al. Diabetes Care. 2013;36: ; 6. Meier JJ, et al. Diabetes Care. 2015;38:

32 Shared Decision-Making Points for Comparing a GLP-1 Receptor Agonist vs a Prandial Insulin Analogue Aspect of Care Number of additional injections, per week Dose adjustment for meals required? Dose adjustment for exercise required? Glucose monitoring needed multiple times daily? GLP-1 Receptor Agonist (GLP-1 RA) Prandial Insulin Analogue 1to 14 7to 21 No No No Yes Yes Yes Drugs@FDA. Scripts/cder/DrugsatFDA. Accessed January 8, 2016.

33 Investigational Coformulations of Basal Insulin and a GLP-1 RA Offer Potential for Intensifying Basal Insulin Therapy With a Single Daily Injection Coformulated a Liraglutide +Degludec 1,b vs Degludec vs Liraglutide Coformulated a Lixisenatide + Glargine 2,c vs Glargine Composite endpoint: A1C < 7% without weight gain or hypoglycemia a Not US FDA approved; b Baseline A1C, 8.3%; Baseline Wt, 87 kg; 26 weeks; c Baseline A1C, 8.0%; BL BMI, 32.1 kg/m 2 ; 24 weeks; * P <.0001 vs DEG; P <.0001 vs LIRA; P <.05 vs PBO + GLAR. All baseline characteristics stated as means values. 1. Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2: Rosenstock J, et al. Diabetologia. 2014;57(suppl 1):S108 [abstract 241].

34 Summary U-100 Glargine Equivalent 100 units/ml Biologically equivalent to U- 100 glargine Compared with U-100 glargine: Equally effective Equivalent hypoglycemia Equivalent weight gain U-300 Glargine 300 units/ml Same molecule as U-100 glargine but more concentrated Compared with U-100 glargine: Equally effective Less hypoglycemia a Equivalent weight gain U-100 and U-200 Degludec 100 or 200 units/ml Novel molecular configuration Compared with U-100 glargine a : Equally effective Less hypoglycemia b Equivalent weight gain U-100 glargine equivalent has the same therapeutic characteristics as U-100 glargine Ultralong-acting basal insulins have a flatter time-action profile, with less glycemic variability, and may be less likely to cause hypoglycemia than first-generation insulin analogues a Significantly less overall hypoglycemia in insulin-naive patients. b Significantly less nocturnal hypoglycemia in insulin-naive patients.

35 Summary Prandial Insulins Improve glycemic control Greatest flexibility Stepwise initiation minimizes risks of hypoglycemia and weight gain Premixed insulin may be an appropriate alternative for some patients GLP-1 Receptor Agonists Improve glycemic control Potentially fewer daily injections than prandial insulin Low risks of hypoglycemia or weight gain Prescribing limitations in some patients

36 Summary Most patients with T2DM will eventually need insulin therapy Insulin is recommended throughout the progression of T2DM Earlier insulin use is associated with better long-term glycemic control than postponed insulin use With appropriate dose adjustment, insulin can be used alone or in combination with other antihyperglycemic agents in essentially all patients Insulin offers unmatched flexibility to individualize glycemic control, with 18 products in 7 different time-action categories