beyond basal insulin: intensification of therapy · beyond basal insulin: intensification of...

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

Disclosures

• Jennifer D’Souza has no conflicts of interest to disclose.

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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…

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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.

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US FDA-Approved Therapies To Be Combined with Basal Insulin

Class Agents with FDA Approval for Use in Combination with Insulin

Thiazolidinediones (TZD)

• Pioglitazone • Rosiglitazone

US FDA. Drugs@FDA Web site. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/

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Class Agents with FDA Approval for Use in Combination with Insulin

DPP-4 inhibitors

• Alogliptin • Linagliptin • Saxagliptin • Sitagliptin


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DPP-4 Inhibitors as Add-on Therapy to Basal Insulin (With or Without Oral Agents)

-0.6 -0.6 -0.6 -0.71

0

-0.2

0.1

-0.1

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

0.2Sitagliptin¹ Saxagliptin² Linagliptin³ Alogliptin⁴

Δ in

A1C

, %

Basal insulin, add DPP-4 inhibitor Basal insulin, add placebo

Baseline A1C = 8.5% Δ 0.6%* Δ 0.41%† Δ 0.7%† Δ 0.61%*

* p < 0.001; † p < 0.0001 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%

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DPP-4 Inhibitors and Basal Insulin: Low Risk of Severe Hypoglycemia or Weight Gain

No data

0.6

5.3

1.7 1.0

0.3

3.3

1.0 2.0

0

2

4

6Sitagliptin¹ Saxagliptin² Linagliptin³ Alogliptin⁴

Sev

ere

Hyp

ogly

cem

ia, %

Agent + INS INS + PBO

0.10 0.39

-0.30

0.60

0.10 0.18

-0.04

0.70

-0.6-0.20.20.61.0

Δ W

t, %

of

Bas

elin

e

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. 3. Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881. 4. Rosenstock J, et al. Diabetes Obes Metab. 2009;11:1145-1152.

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Class Agents With FDA Approval for Use in Combination With Insulin

SGLT2 Inhibitors

• Canagliflozin • Dapagliflozin • Empagliflozin


Class Agents with FDA approval for use in combination with insulin

SGLT2 inhibitors

• Canagliflozin • Dapagliflozin • Empagliflozin

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SGLT2 Inhibitors and Basal Insulin: Impact on Hypoglycemia and Body Weight

2.7

0.5 1.3

2.5

0.5 0

0

1

2

3Canagliflozin¹ Dapagliflozin² Empagliflozin³

Sev

ere

Hyp

ogly

cem

ia,%

Agent + INS PBO + INS

Proportion of patients attaining A1C <7% with SGLT2 inhibitors, in combination with basal insulin, ranged from 11% to 25%¹-³

-2.3* -1.8* -1.8†

0.1 0.0

-0.1

-6-4-202

Δ W

t, %

of

Bas

elin

e

1. Neal B, et al. Diabetes Care. 2015;38:403-411. 2. Cefalu WT, et al. Diabetes Care. 2015;38:1218-1227. 3. Rosenstock J, et al. Diabetes Obes Metab. 2015;17:936-948.

* p < 0.001 vs. placebo; † p < 0.01 vs. placebo 12

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

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

FDA News Release (SGLT2). Available at: http://www.fda.gov/drugs/drugsafety/ucm446845.htm. 13

• 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 Pre-breakfast Pre-dinner 2-hr post-

dinner 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

Case Study: Introduction (cont’d)

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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 Pre-breakfast

Pre-dinner

2-Hr post-dinner

Bedtime Comments

Sun 138 145 195 188

Mon 132 155 205 196 Increased basal

insulin dose by 4 units

Tues 120 135 188 182 Forgot to inject

his insulin

Wed 145 168 230 198

Thurs 132 140 200 186 Increased basal

insulin dose by 2 units

Fri 125 142 175 161

Sat 112 128 185 173

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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

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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.

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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%

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%

Additive effects

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.

PPG = postprandial FPG = fasting plasma glucose

Complementary actions

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

More Than 2 Daily Injections

• Temptation is to split basal dose and give it twice a day

As type 2 patients require larger doses of basal insulin (>0.5 units/kg)

• Keep basal once daily, and • Add a rapid acting insulin injection with largest meal • Follow a dosing algorithm • Follow the 90/10 rule

If going to 2 injection insulin program

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.

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90/10 Rule for Basal+1

90% basal, 10% rapid-acting (bolus)

Start with largest meal of the day

When initiating rapid-acting insulin: • Always stop the

sulfonylurea • Often stop

thiazolidinedione • Consider adjusting the

doses of other antidiabetic medications


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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 Glycemic Treatment . Diabetes Care 2017;40(Suppl. 1):S64-S74. Inzucchi SE, et al. Diabetes Care. 2015;38:140–149.

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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.

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Timing of Bolus Insulin Injections

Add rapid-acting

insulin at breakfast

Pre-lunch:

Add long-acting at

breakfast or rapid-acting

insulin at lunch

Pre-dinner:

Add rapid-acting

insulin at dinner

Pre-bedtime:

Nathan DM, et al. Diabetes Care. 2009;32:103-203.

Based on preprandial levels:

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Types of Insulin: Prandial (Meal-Related)

Type of insulin Onset of action Peak of action Duration

of action Presentation

Rapid-acting insulin analog Insulin lispro (U100, U200) 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.

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LIS 0.2 U/kg (n = 10) Regular human insulin (n = 10); mean dose, 15.4 U

0 240 360 480 300 420 Time, min

120 180 60

80 70

50

30

0 10 20

40

60

Ser

um fr

ee in

sulin

co

ncen

tratio

n, m

U/L

U-200 Lispro • Pharmacokinetics • Pharmacodynamics

http://www.prnewswire.com/news-releases/us-food-and-drug-administration-approves-humalog-200-unitsml-kwikpen-300089341.html

Potential advantage: smaller injection volume for those with high prandial insulin requirements

0 240 360 480 300 420 Time, min

120 180 60

250

200

150

100

0

Pla

sma

gluc

ose,

mg/

dL

50

LIS 0.2 U/kg (n = 10) Regular human insulin (n = 10); mean dose, 15.4 U

PK/PD data generated from a study of 10 patients with T1DM 30

Inhaled Insulin (Technosphere) in T2DM

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

5.0

3.0

1.0 GIR

, mg/

kg/m

in

0 60 120 180 Time, min

4.0

2.0

0.0 240 300 360 420 480 540

• 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

1. Rave K, et al. J Diabetes Sci Technol. 2008;2:205-212. 2. Rosenstock J, et al. Diabetes Care. 2015;38:2274-2281.

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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

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Types of Insulin: Premixed

Type of insulin Onset of action

Peak of action

Duration of action Presentation

NPH/Regular 70/30 or 50/50 30-60 min Dual 10-16 hour Vial, pen/ cartridge

Insulin Aspart Protamine/Insulin Aspart 70/30 10-20 min Dual 15-18 hour Vial, pen

Insulin Lispro Protamine/Insulin Lispro 75/25 or 50/50 5-15 min Dual 16-18 hours Vial, pen/

cartridge Insulin Degludec/Insulin Aspart 70/30 10-20 min Dual 42 hours Pen


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When Basal Insulin Is Not Enough - SUMMARY

• Inadequate control despite effectively titrated basal insulin (FBG >130 mg/dL, A1C >7%)

• Basal dose is ≥0.5 U/kg/day

Know when additional therapy beyond basal insulin is needed

• Avoid hypoglycemia • Therapies favorable to weight reduction and

blood pressure • Agents that specifically address post-prandial glucose excursions

Consider TZD, DPP-4 i, or GLP-1 RA as an additive to basal insulin

Adding a rapid-acting insulin or premixed insulin in a step-wise method before meals

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Thank You!

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beyond basal insulin: intensification of therapy · beyond basal insulin: intensification of...

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