Optimal Use of Insulin In Type 2 Diabetes Martin J. Abrahamson, MD - PowerPoint PPT Presentation

Optimal Use of Insulin In Type 2 Diabetes Martin J. Abrahamson, MD FACP Associate Professor of Medicine, Harvard Medical School

Learning objectives Review the pharmacokinetics of the insulins used in clinical practice Discuss initiation and intensification of basal insulin in type 2 diabetes (T2DM) Discuss use of insulin and GLP1 RA in type 2 diabetes Discuss use of prandial insulin in diabetes

Physiologic Insulin Secretion: 24-hour Profile 50 Insulin (µU/mL) 25 Basal insulin 0 Breakfast Lunch Dinner 150 100 Glucose (mg/dL) 50 Basal glucose 0 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 AM PM Time of day

Insulins Available for Clinical Use • Prandial insulin • Short acting - Regular • Rapid acting analogues - Aspart, Lispro, Apidra • Basal Insulin • NPH • Basal analogues • U 100 Glargine, Detemir • U 300 Glargine, Degludec • Premixed insulins • Provide both basal and meal time cover

Pharmacodynamics of different insulins Rapid (Lispro, Aspart, Glulisine) Short (Regular) Insulin level NPH Basal long (Detemir and U 100 Glargine) Basal ultralong (Degludec and U 300 Glargine) Hours 0 2 4 6 8 10 12 14 16 18 20 22 24 Hours after injection ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015

Ultra-fast insulin: Even closer to a physiological insulin profile Ultra-fast insulin should: From the normal pancreas Better approach physiological insulin • Insulin action (at mealtime)* secretion in T1D Ultra-fast insulin Replace early insulin secretion in T2D • Rapid-acting insulin Have a better profile for pump therapy • Regular human insulin Time (h) *Schematic representation T1D, type 1 diabetes; T2D, type 2 diabetes Adapted from Home. Diabetes Obes Metab 2015;17:1011 – 20

Changing the formulation: Faster aspart is insulin aspart in a new formulation Niacinamide: absorption modifier Vitamin B3 L-Arginine: added for stability Insulin aspart Naturally-occurring amino acid FDA. Inactive Ingredient Search for Approved Drug Products database. www.accessdata.fda.gov/scripts/cder/iig/index.cfm

Inhaled Technosphere Insulin ► “Ultra -rapid- acting” inhaled insulin: ► Onset 12-15 minutes  Peak 60 minutes  Duration 2.5-3 hours RAA = Rapid-acting analog GIR = Glucose infusion rate Santos Cavaiola T, Edelman S. Clin Ther. 2014;36:1275-1289 ; Afrezza Package insert

The Ideal Basal Insulin • Mimics normal pancreatic basal insulin secretion • Long-lasting effect – 24 hours • Smooth, peakless profile • Reproducible and predictable effects • Reduced risk of nocturnal hypoglycemia • Once-daily administration

24 hour Plasma Glucose Curve: Rationale for Adding Basal Insulin 400 Glucose (mg/dL) Diabetes 300 200 Normal 100 0 0600 1000 1400 1800 2200 0200 0600 Time of Day Adapted from Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.

24 hour Plasma Glucose Curve: Rationale for Adding Basal Insulin 400 300 Glucose (mg/dL) 200 Diabetes 100 Normal 0 0600 1000 1400 1800 2200 0200 0600 Time of Day Adapted from Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.

Basal Insulin Added to Oral Agents Improves HbA 1c 9.5 Detemir 9.0 NPH Glargine 8.5  1.7  1.5 HbA 1c (%) 8.0  1.6  1.6  1.9  1.8 7.5 7.0 6.5 0 Riddle 2003 Hermansen 2006 Philis-Tsimikas 24 weeks 24 weeks 2006 20 weeks p =ns for all

Are all basal insulin analogs the same? NO!

The quest for the ideal basal insulin - From NPH to basal insulin analogues IDet Animal Isolation of insulin insulin preparations (Banting & Best) NPH insulin IGlar U100 IGlar U300 IDeg Ultra-long-acting First generation basal insulin basal insulin analogues analogues λ 18 – 19 5 – 10 12.5 25 Half life (hours): High Medium Low Variability: IDet insulin detemir; NPH, neutral protamine Hagedorn Kalra. J Pak Med Assoc 2013;63:1442 – 4 ; Insulatard SmPC; Toujeo SmPC

Lower day-to-day glucose variability with first-generation basal insulin analogues versus NPH 6 6 6 GIR (mg/kg/min) NPH 0.4 U/kg 4 4 4 IGlar U100 0.4 U/kg 100 IDet 0.4 U/kg 2 2 2 Intra-patient variability (CV%) 0 0 0 0 8 16 24 0 8 16 24 0 8 16 24 80 6 6 6 GIR (mg/kg/min) 68 4 4 4 60 2 2 2 48 0 0 0 40 0 8 16 24 0 8 16 24 0 8 16 24 6 6 6 GIR (mg/kg/min) 27 20 4 4 4 2 2 2 0 0 0 0 NPH IGlar U100 IDet 0 8 16 24 0 8 16 24 0 8 16 24 Time (hours) Time (hours) Time (hours) CV, coefficient of variation; GIR, glucose infusion rate; IDet, insulin detemir; IGlar U100, insulin glargine U100 Heise et al. Diabetes 2004;53:1614 – 20

Reduced risk of hypoglycemia with first-generation basal insulin analogues versus NPH 1.0 Relative risk of confirmed Type 2 diabetes 0.9 hypoglycaemic events IGlar U100 0.8 * IDet * 0.7 * * * 0.6 * 0.5 Approximate risk- * 0.4 * 0.3 reduction range T2D: 2 to 53% T1D: – 20% to 46% 1.2 Relative risk of nocturnal hypoglycaemic events 1.0 Type 1 diabetes 0.8 * 0.6 * * * * * * 0.4 * * * 0.2 Hypoglycaemia definition varies across studies; direct comparisons cannot be made. Studies with two arrows compared different dosing times for IGlar U100 or IDet *Significant difference; †Not treat -to-target; T1D, type 1 diabetes; T2D, type 2 diabetes Devries et al. Diabetes Metab Res 2007;23:441 – 54; Fajardo Montanaña et al. Diabet Med 2008;25:916 – 23; Horvath et al. Cochrane Database Syst Rev 2007;18:CD005613; Robertson et al Diabet Med 2007;24:27 – 34; Bartley et al. Diabet Med 2008;25:442 – 9; Pieber et al. Diabet Med 2007;24:635 – 42

U300 Glargine (Toujeo) vs U100 Glargine: Equally effective but with higher dose of U300 Glargine Yki Jarvinen H et al. Diabetes, Obesity and Metabolism 17: 1142 – 1149, 2015.

U300 Glargine is associated with less hypoglycemia than U100 glargine Yki Jarvinen H et al. Diabetes, Obesity and Metabolism 17: 1142 – 1149, 2015.

N Engl J Med 377: 723 – 732

Primary and secondary confirmatory endpoints Time from randomization to first occurrence of a 3-point MACE: cardiovascular death* † , non-fatal myocardial Primary endpoint infarction* or non-fatal stroke* • Number of severe hypoglycemic episodes* Secondary confirmatory endpoints • Incidence of severe hypoglycemic episodes* Marso S.P., McGuire D.K., Zinman B., et al. N Engl J Med 2017; 377:723-732 *Confirmed by the Event Adjudication Committee. †Cardiovascular death includes undetermined cause of death.

Key inclusion criteria: cardiovascular profile High cardiovascular Type 2 diabetes • Cardiovascular or risk profile chronic kidney disease and aged ≥50 Current treatment with ≥1 oral or injectable antidiabetic agent(s) OR • Risk factors for HbA 1c <7.0% and cardiovascular or HbA 1c OR current basal insulin chronic kidney disease ≥7.0% treatment ≥20 U/day and aged ≥60 Marso S.P., McGuire D.K., Zinman B., et al. N Engl J Med 2017; 377:723-732

Similar mean HbA 1c 75 9.0 Insulin degludec Insulin degludec IGlar U100 IGlar U100 0.0 69 8.5 HbA 1c (mmol/mol) 64 8.0 HbA 1c (%) -0.5 59 7.5 -0.84 -0.86 53 7.0 -1.0 Post hoc ETD: 0.01% 0 6.5 [ – 0.05; 0.07] 95% CI 0 3 6 9 12 15 18 21 24 27 30 ET Months since randomisation Insulin degludec (N) 3774 Insulin degludec (N) 3774 3656 3656 3608 3608 3535 3535 3525 3525 2458 2458 3344 3344 IGlar U100 (N) 3776 IGlar U100 (N) 3776 3640 3640 3562 3562 3516 3516 3500 3500 2424 2424 3277 3277 Full analysis set. Bar graph shows observed mean change from baseline at month 24 (%). ET, end treatment visit; ETD, estimated treatment difference

Event rate Time to first 3-point MACE 4.71/100 patient-years of observation 12 Insulin degludec N=356 Patients with an event (%) IGlar U100 N=325 10 8 HR: 0.91 [0.78; 1.06]95% CI 6 Non-inferiority confirmed 4 Event rate 4.29/100 patient-years of observation 2 0 0 3 6 9 12 15 18 21 24 27 30 Time to first EAC-confirmed event (months) Insulin degludec (N) 3818 3765 3721 3699 3611 3563 3504 2851 1767 811 217 IGlar U100 (N) 3819 3758 3703 3655 3595 3530 3472 2832 1742 811 205 Marso S.P., McGuire D.K., Zinman B., et al. N Engl J Med 2017; 377:723-732

Rates of severe hypoglycemia Insulin degludec IGlar U100 RR: 0.60 0.16 Mean number of episodes per [0.48; 0.76] 95% CI p <0.001 0.12 patient 0.08 0.04 0.00 0 3 6 9 12 15 18 21 24 27 30 Time from randomisation (months) Insulin degludec IGlar U100 (N=3819) And 53% reduction in severe nocturnal hypoglycemia (N=3818) E R E R Confirmed episodes 280 3.70 472 6.25 Marso S.P., McGuire D.K., Zinman B., et al. N Engl J Med 2017; 377:723-732

Combining a GLP-1 RA and a basal insulin in one pen improves efficacy and safety Efficacy Side effects HbA 1c FPG PPG WEIGHT HYPOGLYCEMIA NAUSEA GLP-1 RA/basal insulin Basal insulin GLP-1 RA monotherapy combined in one pen For illustrative purposes only, not drawn to scale GLP-1 RA, glucagon-like peptide-1 receptor agonist; FPG, fasting plasma glucose; PPG, postprandial glucose 1. Inzucchi et al. Diabetes Care 2015;38:140 – 9; 2. Garber et al. Endocr Pract 2016;22:84 – 113