1 Successful Transition to Insulin Therapy in T2DM Merri Pendergrass, M.D., Ph.D. Endocrinology, University of Arizona All Faculty, CME Planning Committee.

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Successful Transition to

Insulin Therapy in T2DM

Merri Pendergrass, M.D., Ph.D.

Endocrinology, University of Arizona

All Faculty, CME Planning Committee Members, and the CME Office Reviewer have disclosed that they have no financial relationships with commercial interests that would constitute a conflict of interest concerning this CME activity.

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Learning Objectives

Participants should be better able to

• Select a strategy for insulin initiation• Intensify an insulin regimen• Understand available modalities (e.g.

vials, pens) for insulin administration

54 year old patient with T2DM

a. Pioglitazone (Actos®)b. Exenatide (Byetta®)c. Sitagliptin (Januvia®)d. Canaglifozin (Invokana®)e. Insulin

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• On metformin 1000 bid, glipizide 10 qd• A1C 9.1

What would you add now?

54 year old patient with T2DM

a. Pioglitazone (Actos®)b. Exenatide (Byetta®)c. Sitagliptin (Januvia®)d. Canaglifozin (Invokana®)e. Insulin

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• On metformin 1000 bid, glipizide 10 qd• A1C 9.1

What would you add now?

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Approximate A1C Lowering

Metformin

~ A1C Reduction (%)

1.0-2.01.0-2.0

Byetta, Bydureon, Victoza

Januvia,Onglyza,Tradjenta,Nesina

SulfonylureaAvandia, Actos 0.5-1.5

0.5-1.5

0.5-0.8Invokana 0.8-1.0

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Insulin for Type 2 Diabetes

• Safe and effective option • Not a last resort • Can decrease any level of A1C to goal• Indicated if not controlled on non-insulins

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Improving Insulin Acceptance

• Don’t threaten as a punishment• Address patient concerns/pre-

conceptions, e.g.– Not a personal failure– Complications are not inevitable– Can potentially stop insulin later

• Consider insulin pens

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Profiles of Available Insulins In

sulin

Effe

ctNPH

Glargine (Lantus)Regular

0 6 12 18 24

Time (hours)

Detemir (Levemir)

Lispro (Humalog)Aspart (Novolog)Glulisine (Apidra)

Basal

BolusNutritionalCorrection

Which regimen will you start?

a. NPH at bedtime

b. Lantus® at bedtime

c. NPH/regular bid ac

d. NPH at bedtime + regular tid ac

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Which regimen will you start?

a. NPH at bedtime

b. Lantus® at bedtime

c. NPH/regular bid ac

d. NPH at bedtime + regular tid ac

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Same Effects in T2DM with Insulin Given QD, BID, or QID

-0.5

-1.7 -1.9 -1.8-1.6-2

-1

0

1

2

Change in A1C (%)

ControlAM

NPHQID N/R

HS NPH

BID NPH

Yki-Jarvinen H, et al. N Engl J Med. 1992;327:1426-1433.

* * * *

Least weight gain

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Evidence Supports Initiating Insulin…

Type RegimenNPH

QD, BIDGlargine

Detemir

Lispro, aspart, glulisine TID

Pre-mix QD, BID, TID

Other combinations QD, BID, TID, QID

Sequential Insulin Strategies in T2DM diabetes.

Inzucchi S E et al. Dia Care 2012;35:1364-1379

Copyright © 2011 American Diabetes Association, Inc.

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Initiating Basal Insulin

• ~50% patients achieve A1C< 7% with basal insulin given at bedtime

• For T2DM, effects are similar for qHS– NPH– Glargine (Lantus®)– Detemir (Levemir®)

$

$$

$$

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Insulin Cost*

Item Cost ($) / Item

$/1000 units (~33 units/day)

NPH 10 ml vial 24.88 24.88

NPH Box of 5 (3 ml pens) 294.28 196.18

Lantus 10 ml vial 226.68 226.68

Lantus Box of 5 (3 ml pens) 351.62 234.41

U500 20 ml vial 1130.00 113.00

*Walmart 2/8/14

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The Treat-to-Target Trial NPH vs. Glargine (Lantus®)

Mean FBG on Preceding 2 Days

Increase in Insulin Dosage

> 180 8

140-180 6

120-140 4

100-120 2

Start With 10 IU Insulin qHS & Adjust Weekly

Riddle et al, Diabetes Care 26, 3080-3086, 2003

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qHS NPH and qHS Lantus® have Similar Effects on A1C, FPG

(T2DM)

Riddle et al, Diabetes Care 26, 3080-3086, 2003

0 4 12 16 20 248

150

200

0 4 12 16 20 248

7

8

6

9

A1

C (

%)

FP

G (

mg

/dl)

NPHGlargine (Lantus)

Slightly Less Hypoglycemia: with Glargine (Lantus) vs. NPH

17.7

5.12.5

13.9

31.8

0

5

10

15

20

< 72 mg/dl <56 mg/dl Severe

Num

ber

of

even

ts/p

atie

nt/y

ear

NPH Lantus

Riddle et al, Diabetes Care 26, 3080-3086, 2003

*

**

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Key Factor Contributing to the Success of the Regimen

• Not what type of insulin is used• Not how many doses are used• Not what is the initial starting dose• Success depends on

– Adherence– How regularly and rapidly insulin is

adjusted to achieve targets!

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Start NPH 20 units at bedtime and increase by 10 units every week if average fasting glucose is above 100 and no hypoglycemia (BG <72)

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Start NPH 10 units at bedtime and increase by 2 units every night if fasting glucose is above 100 and no hypoglycemia (BG < 72)

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Insulin Titration: MD Vs. Patients

Titrated by MD(N=2315)

Titrated by Patient(N=2273)

≥ 100 to < 120 0-2* 0-2*

≥ 120 to < 140 2 2

≥ 140 to < 180 4 2

≥ 180 6-8 2

Start with 10 units glargine qHS

*Only increase if no values < 72Diabetes Care 28:1282-1288, 2005

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Patient and MD Insulin Titration Yield Similar Results

0

5

10

15

20

25

30

35

Severe Symptomatic Nocturnal

Incidence of Hypoglycemia

(%)

MD Titration Patient Titration

77.27.47.67.8

88.28.48.68.8

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MD Titration Patient Titration

A1C (%)

Baseline 24 Weeks

Diabetes Care 28:1282-1288, 2005

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Question:• Patient on metformin, NPH 60 hs• A1C 8.0• SMBG

– Ac breakfast 80-100– Ac lunch 80-100– Ac dinner 80-120– HS 200-250

What would you do? a. Change from NPH to glargine (Lantus)b. Increase NPH to 70c. Add NPH in AMd. Add lispro (Humalog) ac dinner

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Question:• Patient on metformin, NPH 60 hs• A1C 8.0• SMBG

– Ac breakfast 80-100– Ac lunch 80-100– Ac dinner 80-120– HS 200-250

What would you do? a. Change from NPH to glargine (Lantus)b. Increase NPH to 70c. Add NPH in AMd. Add lispro (Humalog) ac dinner

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Patient now on metformin, insulin

• Meds: metformin 1 g bid, NPH 60 hs• A1C 8.0• SMBG

– Before breakfast 80-100– Before lunch 80-100– Before dinner 80-120– Before bedtime 200-250

Best to add rapid-acting insulin ac dinner

Would NOT increase NPH HS (risk for AM hypoglycemia)

Would NOT Add NPH AM (risk for daytime hypoglycemia)

Would NOT change NPHglargine: (glargine = NPH for A1C changes)

278 12 6 10

Matching Insulin to Basal and Nutritional Needs

50 year old patient with T2DM,BMI 40.1, A1C 12, FPG 250,Metformin 1 g bid, 70/30 100 bid

What is your next step?

a) Increase to 70/30, 150 bid

b) Increase to 70/30, 100 tid

c) Split each dose into 2 injections

d) Stop 70/30, start U-500 regular insulin

50 year old patient with T2DM,BMI 40.1, A1C 12, FPG 250,Metformin 1 g bid, 70/30 100 bid

What is your next step?

a) Increase to 70/30, 150 bid

b) Increase to 70/30, 100 tid

c) Split each dose into 2 injections

d) Stop 70/30, start U-500 regular insulin

Strategies to Get “More Insulin Into” Insulin Resistant Patients

• Add additional injections, e.g. 70/30 three time a day

• Split large doses into 2 injections (smaller depot = better absorption)

• Use more concentrated insulins, e.g. U-500

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U-500 is Five Times as Concentrated as U-100 Insulin

• U-100 = 100 units/ml • U-500 = 500 units/ml• 1 ml U-100 = 100 units = 0.2 ml U-500• U-500 should be considered when total

daily dose (TDD) insulin is > 200 units• Initial dosing ~ BID

ENDOCRINE PRACTICE Vol 15 No. 1 January/February 2009

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U500 Lets Patient Inject Less

u100

u500

100 units

100 units

Convert Insulin Units U-500 cc: Divide Units by 500

125 units insulin = ?? cc u500

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150 units insulin =

1 cc

125 units insulin

500 units insulin.25 cc

150 / 500 = .30 cc

175 units insulin = 175 / 500 = .35 cc

Convert U-500 cc Units Insulin: Multiply cc by 500

.30 cc u500 = ?? units insulin

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.35 cc u500 =

500 units insulin

.30 cc u500

1 cc u500150 units

insulin

.35 X 500 = 175 units

.15 cc u500 = .15 X 500 = 75 units

Include Two Identifiers of Correct Dose on Prescriptions

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U500 insulin:Sig: Pull to the 25 unit mark (125 units) before breakfast and pull to the 20 unit mark (100 units) before dinner

Better Control with u500

N = 53, 6-52 months f/u Baseline (u-100)

End (u-500)

A1C (%) 9.1 8.1*Insulin dose (units) 391 415*Weight (kg) 134 136Cholesterol (mg/dL) 176 156*TG (mg/dL) 349 252*Severe hypoglycemia (total events in first 12 months f/u) 3 3

36Endocr Pract. 2011 Jul 8:1-15. * P < 0.05

Additional Insulin Concentrations May Become Available Soon

• Insulin degludec (TresibaTM)– Approved in the EU and Japan – Under regulatory review in the US– Developed both as a 100-unit/ml

formulation and a 200-unit/ml formulation

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70/30 Effective When Given Once, Twice, or Thrice a Day

QD BID TID0

10

20

30

40

50

60

70

80

90

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7077

Percentage of Patients with A1C<7

38Diabetes, Obesity and Metabolism, 8, 2006, 58–66

Splitting Large Volume into Two Injection Sites May Improve Effect

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100 units (1.0 ml)

50 units(o.5 ml)

50 units(0.5 ml)

Depots more than ~ .6 ml not well absorbed

Better Absorption

High Dose Insulin More Effective Injected in Two vs. One Site

40Saryusz-Wolska M. Abstract #109. EASD; Sept. 12-16, 2011; Lisbon.

1-site injection (240 IU)

2-site injection (254 IU)

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7.5

8

8.5

9

9.5

10

10.5

11

10 10.310.4

8.8

Baseline12months

A1C (%)

Ordering Insulin and Supplies Examples for 90-Day Supply

Vial/syringe = 2 scripts1. NPH 50 units SC qHS,

Disp: 5 vials

2. Syringes, 1 ML 6 MM (15/64”) X 31 G, 100-count box

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90 days X 50 units/day = 4.5 vialsX 1 vial/1000 units

Shorter, thinner needles hurt less!

Ordering Insulin and Supplies Examples for 90-Day Supply

Pen/needles = 2 scripts 1. NPH 50 units SC qHS, Disp: 3 boxes (5 X 3 mL)

2. Pen needles, 4mm x 32G, 100-count box

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300 units

Recommendations - 1

• Start with a single injection of basal insulin at bedtime– NPH has lowest cost and similar clinical

effects as Lantus® and Levemir®

– Insulin pens easier but more expensive• Titrate insulin often to normalize FBG

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Recommendations - 2

• If FBG at goal (~100) and A1C above goal, add an injection of a short-acting insulin before the largest meal– Regular is cheapest but adherence may be

better with Humalog®, Novolog® or Apidra® • Consider adding additional pre-meal

injections, based on BG monitoring

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Recommendations - 3

• Continue metformin• Stop sulfonylureas if insulin dose is

more than ~20-40 units• Consider potential risks and benefits of

continuing other non-insulin agents, e.g. – Multiple agents can get expensive – Not much incremental A1C benefit– Invokana®, Byetta®, Victoza® associated

with weight loss 45

Recommendations - 4

• If A1C is above goal with > 200 units of insulin per day, consider switching to U-500 bid

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Comments or Questions?

[email protected]