Beyond Basal Insulin: Intensification of Therapy Jennifer D Souza, PharmD, CDE, BC-ADM

Beyond Basal Insulin: Intensification of Therapy Jennifer D Souza, PharmD, CDE, BC-ADM

Disclosures Jennifer D Souza has no conflicts of interest to disclose. 2

When Basal Insulin Is Not Enough Learning Objectives Categorize patient characteristics that would assist clinicians in identifying the appropriate management for intensification of insulin therapies in patients with type 2 diabetes Discuss the implications of adverse effects associated with various classes of antihyperglycemic medications Compare and contrast advantages and disadvantages of various strategies used for intensifying insulin therapy Employ clinical practice recommendations from practice guidelines toward the optimal use of different classes of drugs for intensification of insulin therapy in individuals with diabetes 3

Case Study: Introduction Mr. K, a 50-year-old Caucasian male, has had diabetes for 6 years He is concerned about his uncontrolled blood glucose level, a recent increase in weight (5 lbs), and that lately has been feeling anxious and sometimes confused Physical exam: Height 5 9 (152 cm) Weight 198 lbs (90 kg) BMI 29.2 kg/m² BP 138/84 mmhg Continued 4

Case Study: Introduction (cont d) Lab results (recent): A1C 8.1% FPG <130 mg/dl 2-hour postprandial (dinner) >180 mg/dl (~200 mg/dl) Medication history: Metformin 500 mg/glipizide 5 mg: 2 tabs (1000/10) BID Started on insulin glargine last year, titrating to a current dose of 50 units at bedtime (increased by 6 units in the past week) Consults with a registered dietitian and eats a healthy diet Exercises three times a week Continued 5

ADA/EASD Medication Guideline for T2DM Inzucchi SE, et al. Diabetes Care. 2015;38:140 149. American Diabetes Association Standards of Medical Care in Diabetes. Pharmacologic Approaches to Glycemic Treatment. Diabetes Care 2017;40(Suppl. 1):S64-S74. 6

US FDA-Approved Therapies To Be Combined with Basal Insulin Class Thiazolidinediones (TZD) Agents with FDA Approval for Use in Combination with Insulin Pioglitazone Rosiglitazone US FDA. Drugs@FDA Web site. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ 7

US FDA-Approved Therapies To Be Combined with Basal Insulin Class DPP-4 inhibitors Agents with FDA Approval for Use in Combination with Insulin Alogliptin Linagliptin Saxagliptin Sitagliptin US FDA. Drugs@FDA Web site. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ 8

DPP-4 Inhibitors as Add-on Therapy to Basal Insulin (With or Without Oral Agents) Δ in A1C, % 0.2 0.0-0.2-0.4-0.6-0.8-1.0 Basal insulin, add DPP-4 inhibitor Sitagliptin¹ Saxagliptin² Linagliptin³ Alogliptin⁴ 0 0.1-0.2 Basal insulin, add placebo -0.6-0.6-0.6-0.71 Baseline A1C = 8.5% Δ 0.6%* Δ 0.41% Δ 0.7% Δ 0.61%* -0.1 1. Vilsbøll T, et al. Diabetes Obes Metab. 2010;12:167-177. 2. Barnett AH, et al. Curr Med Res Opin. 2012;28:513-523. 3. Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881. 4. Rosenstock J, et al. Diabetes Obes Metab. 2009;11:1145-1152. A1C <7.0%. 13% 5% 17% 7% 20% 8% * p < 0.001; p < 0.0001 9

DPP-4 Inhibitors and Basal Insulin: Low Risk of Severe Hypoglycemia or Weight Gain Severe Hypoglycemia, % Δ Wt, % ofbaseline 1.0 0.6 0.2-0.2-0.6 6 4 2 0 Sitagliptin¹ Saxagliptin² Linagliptin³ Alogliptin⁴ 5.3 0.6 0.10 Agent + INS 0.3 1. Vilsbøll T, et al. Diabetes Obes Metab. 2010;12:167-177. 2. Barnett AH, et al. Curr Med Res Opin. 2012;28:513-523. 3. Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881. 4. Rosenstock J, et al. Diabetes Obes Metab. 2009;11:1145-1152. No data 3.3 0.39 0.10 0.18 INS + PBO 1.7-0.30 1.0-0.04 1.0 0.60 2.0 0.70 The proportion of patients attaining A1C <7% with sitagliptin, alogliptin, or linagliptin in combination with basal insulin ranged from 8% to 20%;¹ no data for saxagliptin 10

US FDA-Approved Therapies To Be Combined with Basal Insulin Class SGLT2 Inhibitors inhibitors Agents With with FDA Approval approval for Use use in Combination combination With with insulin Insulin Canagliflozin Dapagliflozin Empagliflozin US FDA. Drugs@FDA Web site. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ 11

Severe Hypoglycemia,% Δ Wt, % of Baseline SGLT2 Inhibitors and Basal Insulin: Impact on Hypoglycemia and Body Weight 3 2 1 0 2 0-2 -4-6 Agent + INS Canagliflozin¹ Dapagliflozin² Empagliflozin³ 2.7 2.5 0.5 0.5 0.1 0.0 PBO + INS Proportion of patients attaining A1C <7% with SGLT2 inhibitors, in combination with basal insulin, ranged from 11% to 25%¹ - ³ 1.3-2.3* -1.8* -1.8 1. Neal B, et al. Diabetes Care. 2015;38:403-411. 2. Cefalu WT, et al. Diabetes Care. 2015;38:1218-1227. * p < 0.001 vs. placebo; p < 0.01 vs. placebo 12 3. Rosenstock J, et al. Diabetes Obes Metab. 2015;17:936-948. 0-0.1

SGLT2 Inhibitors and Potential Risk of Diabetic Ketoacidosis The EMA will review incidences of ketoacidosis in patients using SGLT2 inhibitors The focus will be on dapagliflozin, canagliflozin, empagliflozin, canagliflozin/metformin, and dapagliflozin/metformin This follows a warning issued by the FDA on May 15, 2015 FDA regarding the potential risk of ketoacidosis with SGLT2 inhibitors FDA News Release (SGLT2). Available at: http://www.fda.gov/drugs/drugsafety/ucm446845.htm. 20 cases of diabetic acidosis, reported as diabetic ketoacidosis, ketoacidosis, or ketosis, were recorded in patients treated with SGLT2 inhibitors between March 2013 and June 2014 13

Case Study: Introduction (cont d) Mr. K had enjoyed good glucose control for 6 months with a metformin 500 mg/glipizide 5 mg: 2 tablets (1000/10) BID and a stable dose of basal insulin glargine 36 units at bedtime A few weeks ago, his post-dinner blood glucose levels increased, prompting him to increase in his basal insulin dose, which is now 50 units His blood glucose diary shows the following: Day Prebreakfast Pre-dinner 2-hr postdinner Bedtime Comments Sun 138 145 195 188 Mon 132 205 196 Increased basal insulin dose by 4 units Tues 120 135 182 Forgot to inject his insulin Wed 145 168 230 198 Thurs 132 186 Increased basal insulin dose by 2 units Fri 142 175 Sat 112 128 173 14

Case Study - Discussion Question From Mr. K s diary, which plasma glucose patterns of hyperglycemia are present? A. Fasting B. Preprandial C. Postprandial D. Nocturnal E. B and C above Day Prebreakfast Predinner 2-Hr postdinner Bedtime Sun 138 145 195 188 Mon 132 155 205 Tues 120 135 188 Wed 145 168 230 198 Thurs 132 140 200 Fri 125 142 175 161 Sat 112 128 185 173 Comments 196 Increased basal insulin dose by 4 units 182 Forgot to inject his insulin 186 Increased basal insulin dose by 2 units 15

Case Study - Discussion Question A drug from which of the following drug classes could you consider to intensify Mr. K s treatment beyond basal insulin to manage his dysglycemia? A. GLP-1 receptor agonist B. DPP-4 inhibitor C. SGLT2 inhibitor D. Rapid-acting insulin before the main meal E. A, B, C, or D above 19

When Basal Is Not Enough American Diabetes Association Standards of Medical Care in Diabetes. Glycemic Targets. Diabetes Care 2017;40(Suppl. 1):S64- S74. Inzucchi SE, et al. Diabetes Care. 2015;38:140 149. 20

Basal Insulin + GLP-1 Receptor Agonists

Scientific Rationale for Combining a GLP-1RA with Basal Insulin GLP-1 receptor agonist¹, ² Simple to initiate Pronounced PPG control Reduced risk of hypoglycemia Weight reduction Achieve A1C targets in 40-60% Additive effects Basal insulin analogs³, ⁴ Simple to initiate Control nocturnal and FPG Lower hypoglycemia risk vs NPH Modest weight gain (1-3 kg) Achieve A1C target in 40% Complementary actions PPG = postprandial FPG = fasting plasma glucose 1. Holst JJ, et al. Mol Cell Endocrinol. 2009;297:127-136. 2. Calabrese D. Am J Manag Care. 2011;S52-S58. 3. Liebl A. Curr Med Res Opin. 2007;23:129-132. 4. Gugliano D, et al. Diabetes Care. 2011;34:510-517. 22

Basal (long-acting) insulin daily + bolus (rapid-acting) insulin before meals

More Than 2 Daily Injections As type 2 patients require larger doses of basal insulin (>0.5 units/kg) Temptation is to split basal dose and give it twice a day If going to 2 injection insulin program Keep basal once daily, and Add a rapid acting insulin injection with largest meal Follow a dosing algorithm Follow the 90/10 rule Adapted from: American Diabetes Association Standards of Medical Care in Diabetes. Pharmacologic Approaches to Glycemic Treatment. Diabetes Care 2017;40(Suppl. 1):S64-S74. Inzucchi SE, et al. Diabetes Care. 2015;38:140 149. 24

90/10 Rule for Basal+1 90% basal, 10% rapid-acting (bolus) Start with largest meal of the day When initiating rapidacting insulin: Always stop the sulfonylurea Often stop thiazolidinedione Consider adjusting the doses of other antidiabetic medications Adapted from: American Diabetes Association Standards of Medical Care in Diabetes. Pharmacologic Approaches to Glycemic Treatment. Diabetes Care 2017;40(Suppl. 1):S64-S74. Inzucchi SE, et al. Diabetes Care. 2015;38:140 149. 25

Dosing Algorithm for Basal+1 Add 1 rapid-acting insulin injection before largest meal Start: 4 Units, 0.1 U/kg or 10% basal dose. If A1C <8%, consider basal by same amount Adjust: dose by 1-2 units or 10-15% once or twice weekly until SMBG target reached Adapted from: American Diabetes Association Standards of Medical Care in Diabetes. Pharmacologic Approaches to Glycemic Treatment. Diabetes Care 2017;40(Suppl. 1):S64-S74. Inzucchi SE, et al. Diabetes Care. 2015;38:140 149. For hypo: Determine & address causes; if no clear reason for hypo, corresponding dose by 2-4 units or 10-20% 26

Example: 90/10 Rule for Initiating Basal+1 Patient is administering basal insulin 50 units at bedtime Initiating the 90/10 Rule Reduce basal insulin by 10% (i.e., 45 units) Administer 5 units of bolus (rapid-acting) insulin before the largest meal ------------------------------------------ 45 units basal insulin once daily (usually bedtime) Glargine, detemir, degludec, or NPH 5 units bolus before the largest meal Aspart, lispro, glulisine, or regular Adapted from: 1. American Diabetes Association Standards of Medical Care in Diabetes. Pharmacologic Approaches to Glycemic Treatment. Diabetes Care 2017;40(Suppl. 1):S64-S74. 2. Inzucchi SE, et al. Diabetes Care. 2015;38:140 149. 27

Timing of Bolus Insulin Injections Based on preprandial levels: Prelunch: Add rapidacting insulin at breakfast Predinner: Add longacting at breakfast or rapid-acting insulin at lunch Prebedtime: Add rapidacting insulin at dinner Nathan DM, et al. Diabetes Care. 2009;32:103-203. 28

Types of Insulin: Prandial (Meal-Related) Type of insulin Rapid-acting insulin analog Insulin lispro (U100, U200) Onset of action Peak of action Duration of action Presentation 15 min 30-90 min 3-5 hour Vial, pen/cartridge Insulin glulisine 15 min 30-90 min 3-5 hour Vial, pen/cartridge Insulin aspart 15 min 30-90 min 3-5 hour Vial, pen Inhaled insulin 15 min 30-40 min 2-3 hour Inhaler Short-acting insulin Regular, human 30-60 min 120 min 5-8 hour Vial Adapted from: Inzucchi S, et al. Diabetes Care. 2015;38:140-149. FDA Approved Labeling [Package Insert] for each preparation. 29

U-200 Lispro Pharmacokinetics Pharmacodynamics Serum free insulin concentration, mu/l 80 70 60 50 40 30 20 10 0 LIS 0.2 U/kg (n = 10) Regular human insulin (n = 10); mean dose, 15.4 U 0 60 120 180 240 300 360 420 480 Time, min Plasma glucose, mg/dl 250 200 150 100 50 0 LIS 0.2 U/kg (n = 10) Regular human insulin (n = 10); mean dose, 15.4 U 0 60 120 180 240 300 360 420 480 Time, min Potential advantage: smaller injection volume for those with high prandial insulin requirements PK/PD data generated from a study of 10 patients with T1DM 30 http://www.prnewswire.com/news-releases/us-food-and-drug-administration-approves-humalog-200-unitsml-kwikpen-300089341.html

Inhaled Insulin (Technosphere) in T2DM GIR, mg/kg/min 5.0 4.0 3.0 2.0 1.0 Inhaled TI (48 units) SC RHI (24 units) 0.0 0 60 120 180 240 300 360 420 480 540 Time, min 1. Rave K, et al. J Diabetes Sci Technol. 2008;2:205-212. 2. Rosenstock J, et al. Diabetes Care. 2015;38:2274-2281. Duration of action for inhaled insulin is much shorter than for RHI 1 Almost complete PPG suppression has been observed in a double-blind, placebo-controlled trial in insulin-naive patients with T2DM using OADs 2 31

Premixed Insulins Contain both a basal and prandial component, allowing coverage of both basal and prandial needs with a single injection. Regular human insulin and human NPH/Regular premixed formulations (70/30) are less costly alternatives to rapid-acting insulin analogs and premixed insulin analogs, respectively 32

Types of Insulin: Premixed Type of insulin Onset of action Peak of action Duration of action NPH/Regular 70/30 or 50/50 30-60 min Dual 10-16 hour Insulin Aspart Protamine/Insulin Aspart 70/30 Insulin Lispro Protamine/Insulin Lispro 75/25 or 50/50 Insulin Degludec/Insulin Aspart 70/30 Presentation Vial, pen/ cartridge 10-20 min Dual 15-18 hour Vial, pen 5-15 min Dual 16-18 hours Vial, pen/ cartridge 10-20 min Dual 42 hours Pen Adapted from: American Diabetes Association Standards of Medical Care in Diabetes. Pharmacologic Approaches to Glycemic Treatment. Diabetes Care 2017;40(Suppl. 1):S64-S74. Inzucchi SE, et al. Diabetes Care. 2015;38:140 149. 33

When Basal Insulin Is Not Enough - SUMMARY Know when additional therapy beyond basal insulin is needed Inadequate control despite effectively titrated basal insulin (FBG >130 mg/dl, A1C >7%) Basal dose is 0.5 U/kg/day Consider TZD, DPP-4 i, or GLP-1 RA as an additive to basal insulin Avoid hypoglycemia Therapies favorable to weight reduction and blood pressure Agents that specifically address post-prandial glucose excursions Adding a rapid-acting insulin or premixed insulin in a step-wise method before meals 34

Thank You! 35