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Beyond Basal : 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 • 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: • 500 mg/ 5 mg: 2 tabs (1000/10) BID • Started on 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. 6 American Diabetes Association Standards of Medical Care in Diabetes. Pharmacologic Approaches to Glycemic Treatment . Diabetes Care 2017;40(Suppl. 1):S64-S74.

US FDA-Approved Therapies To Be Combined with Basal Insulin

Agents with FDA Approval for Class Use in Combination with Insulin • (TZD) •

7 US FDA. Drugs@FDA Web site. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/ US FDA-Approved Therapies To Be Combined with Basal Insulin

Agents with FDA Approval for Use Class in Combination with Insulin DPP-4 • inhibitors • • •

8 US FDA. Drugs@FDA Web site. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/ DPP-4 Inhibitors as Add-on Therapy to Basal Insulin (With or Without Oral Agents) Basal insulin, add DPP-4 inhibitor Basal insulin, add placebo Sitagliptin¹ Saxagliptin² Linagliptin³ Alogliptin 0.2 0.1 0 ⁴ 0.0 -0.2 -0.1 -0.2 -0.4 in A1C, %

Δ -0.6 -0.6 -0.6 -0.6 -0.8 -0.71 Baseline A1C = 8.5% -1.0 Δ 0.6%* Δ 0.41%† Δ 0.7%† Δ 0.61%* A1C <7.0%. 13% 5% 17% 7% 20% 8%

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. * p < 0.001; † p < 0.0001 9 3. Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881. 4. Rosenstock J, et al. Diabetes Obes Metab. 2009;11:1145-1152. DPP-4 Inhibitors and Basal Insulin: Low Risk of Severe or Weight Gain

Agent + INS INS + PBO Sitagliptin¹ Saxagliptin² Linagliptin³ Alogliptin 6 5.3 ⁴ 4 3.3 No data Severe Severe 1.7 2.0 2 1.0 1.0 0.6 0.3 Hypoglycemia, % Hypoglycemia, 0 1.0 0.60 0.70 0.6 0.39 0.10 0.10 0.18 , % 0.2 -0.2 Wt -0.04 Δ -0.6 -0.30 ofBaseline 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 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. 10 3. Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881. 4. Rosenstock J, et al. Diabetes Obes Metab. 2009;11:1145-1152. US FDA-Approved Therapies To Be Combined with Basal Insulin

AgentsAgents With with FDAFDA Approvalapproval for Useuse inin ClassClass Combinationcombination Withwith insulinInsulin SGLT2SGLT2 •• CanagliflozinCanagliflozin Inhibitorsinhibitors •• DapagliflozinDapagliflozin •• EmpagliflozinEmpagliflozin

11 US FDA. Drugs@FDA Web site. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/ SGLT2 Inhibitors and Basal Insulin: Impact on Hypoglycemia and Body Weight

Agent + INS PBO + INS ¹ ² ³ 3 2.7 2.5

2 1.3 Severe Severe 1 0.5 0.5

Hypoglycemia,% 0 0 2 0.1 0.0 0 -2 -0.1 -1.8* -1.8† Wt, % of

-2.3*

Baseline -4 Δ -6 Proportion of patients attaining A1C <7% with SGLT2 inhibitors, in combination with basal insulin, ranged from 11% to 25%¹-³ 1. Neal B, et al. Diabetes Care. 2015;38:403-411. 12 2. Cefalu WT, et al. Diabetes Care. 2015;38:1218-1227. * p < 0.001 vs. placebo; † p < 0.01 vs. placebo 3. Rosenstock J, et al. Diabetes Obes Metab. 2015;17:936-948. SGLT2 Inhibitors and Potential Risk of Diabetic 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

20 cases of diabetic acidosis, reported as , ketoacidosis, or , were recorded in patients treated with SGLT2 inhibitors between March 2013 and June 2014 13 FDA News Release (SGLT2). Available at: http://www.fda.gov/drugs/drugsafety/ucm446845.htm. 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:

Pre- 2-hr post- Day Pre-dinner Bedtime Comments breakfast dinner 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

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

20 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. Basal Insulin + GLP-1 Receptor Agonists Scientific Rationale for Combining a GLP-1RA with Basal Insulin

Additive effects GLP-1 receptor agonist¹,² Basal insulin analogs³, ●Simple to initiate ●Simple to initiate ⁴ ●Pronounced PPG control ●Control nocturnal and FPG ●Reduced risk of hypoglycemia ●Lower hypoglycemia risk vs NPH ●Weight reduction ●Modest weight gain (1-3 kg) ●Achieve A1C targets in 40-60% ●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. 22 3. Liebl A. Curr Med Res Opin. 2007;23:129-132. 4. Gugliano D, et al. Diabetes Care. 2011;34:510-517. 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 24 Glycemic Treatment . Diabetes Care 2017;40(Suppl. 1):S64-S74. Inzucchi SE, et al. Diabetes Care. 2015;38:140–149. 90/10 Rule for Basal+1

When initiating rapid- acting insulin: • Always stop the 90% basal, 10% Start with largest rapid-acting (bolus) meal of the day • Often stop • Consider adjusting the doses of other antidiabetic medications

Adapted from: American Diabetes Association Standards of Medical Care in Diabetes. Pharmacologic Approaches to 25 Glycemic Treatment . Diabetes Care 2017;40(Suppl. 1):S64-S74. Inzucchi SE, et al. Diabetes Care. 2015;38:140–149. 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

For hypo: Determine & address causes; if no clear reason for hypo, ↓ corresponding dose by 2-4 units or 10-20% Adapted from: American Diabetes Association Standards of Medical Care in Diabetes. Pharmacologic Approaches to 26 Glycemic Treatment . Diabetes Care 2017;40(Suppl. 1):S64-S74. Inzucchi SE, et al. Diabetes Care. 2015;38:140–149. 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 27 Treatment . Diabetes Care 2017;40(Suppl. 1):S64-S74. 2. Inzucchi SE, et al. Diabetes Care. 2015;38:140–149.

Timing of Bolus Insulin Injections

Based on preprandial levels:

Add long- Add Add acting at   rapid-  rapid- Pre- breakfast or Pre- Pre- acting acting dinner: rapid-acting bedtime: lunch: insulin at insulin at insulin at dinner breakfast lunch

28 Nathan DM, et al. Diabetes Care. 2009;32:103-203. Types of Insulin: Prandial (Meal-Related)

Onset of Duration Type of insulin Peak of action Presentation action of action Rapid-acting 15 min 30-90 min 3-5 hour Vial, pen/cartridge (U100, U200) 15 min 30-90 min 3-5 hour Vial, pen/cartridge 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

29 Adapted from: Inzucchi S, et al. Diabetes Care. 2015;38:140-149. FDA Approved Labeling [Package Insert] for each preparation. U-200 Lispro

• • Pharmacodynamics

LIS 0.2 U/kg (n = 10) /L 80 250 LIS 0.2 U/kg (n = 10) 70 Regular human insulin (n = 10); Regular human insulin mU 60 mean dose, 15.4 U 200 (n = 10); mean dose, 15.4 U 50 150 40 30 100 20 50

Serum free Serum free insulin 10 concentration, 0 0

0 60 120 180 240 300 360 420 480 Plasma glucose, mg/dL 0 60 120 180 240 300 360 420 480 Time, min 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

5.0 Inhaled TI (48 units) SC RHI (24 units) 4.0

3.0

2.0 , mg/kg/min 1.0 GIR

0.0 0 60 120 180 240 300 360 420 480 540 Time, min • Duration of action for inhaled insulin is much shorter than for RHI1 • Almost complete PPG suppression has been observed in a double-blind, placebo-controlled trial in insulin-naive patients with T2DM using OADs2 31 1. Rave K, et al. J Diabetes Sci Technol. 2008;2:205-212. 2. Rosenstock J, et al. Diabetes Care. 2015;38:2274-2281. Premixed

• 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

Onset of Peak of Duration of Type of insulin Presentation action action action Vial, pen/ 30-60 min Dual 10-16 hour NPH/Regular 70/30 or 50/50 cartridge Insulin Aspart Protamine/Insulin 10-20 min Dual 15-18 hour Vial, pen Aspart 70/30 Insulin Lispro Protamine/Insulin Vial, pen/ 5-15 min Dual 16-18 hours Lispro 75/25 or 50/50 cartridge /Insulin Aspart 10-20 min Dual 42 hours Pen 70/30

33 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. 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 • 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!

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