insulin regimens

Tuesday, April 11, 2023

1

Objectives

1. Discuss the different types of insulin preparations available to manage types 1 and 2 diabetes

2. Review the various insulin protocols and address appropriate patient selection for each

3. Address how to design and adjust insulin regimens


2

What Type of Insulins Are Available?


3

Normal Pancreas

Insulin is released in response to varying blood glucose levels and hypoglycemia does not occur

Insu

lin

Eff

ect

Basal Insulin (~0.5-1.0 U/hr.)

‘Bolus’ Insulin (Meal Associated)


4

Basal vs Bolus Insulin

BASAL INSULIN• Suppress hepatic glucose

production (overnight and intermeal)

• Prevent catabolism (lipid and protein)– Ketosis– Unregulated amino

acid release• Reduce glucolipotoxicity

BOLUS INSULIN• Meal-associated CHO

disposal

• Storage of nutrients

• Help suppress inter-meal hepatic glucose production


5

Insulin Profiles

Rosenstock J. Clin Cornerstone. 2001;4:50-61.

0 2 4 6 8 10 12 14 16 18 20 22 24

Pla

sma In

sulin

Levels

Time (hr)

NPH (10–20 hr)

Regular (6–10 hr)

Ultralente (~16–20 hr )


6

The Diffusion Of Insulin

Holleman F. NEJM 1997;337(3):176-83Tuesday, April 11, 2023

7

Insulin Self Association Sites


8

Newer Insulins

MODIFCATION

ONSET (hr)

PEAK (hr)

DURATION (hr)

LISPRO (Humalog)

-chain Pro Lys28 -chain LysPro29

0.25-0.5 1-2 3-5

ASPART (NovoLog)

-chain ProAsp28

0.25-0.5 1-2 2-4

GLULISINE (Apidra)

-chain LysAsn 3 -chain LysGlu 29

Similar Simil ar Similar

GLARGINE (Lantus)

-chain AspGly 21 -chain Arg31/Arg32

1 None 24

DETEMIR (Levemir)

-chain Lys29(N-

tetradecanoyl)des( -thr 30) 2 6-8 18

NPH Native insulin complexed with protamine

1-4 8-10 12-20 Tuesday, April 11, 2023

9

Analog Insulin Profiles

Rosenstock J. Clin Cornerstone. 2001;4:50-61.

0 2 4 6 8 10 12 14 16 18 20 22 24

Pla

sma In

sulin

Levels

Time (hr)

NPH (10–20 hr)

Regular (6–10 hr)

Ultralente (~16–20 hr )

Glargine (~24 hr)

Aspart, Lispro, Glulisine (4–5 hr)

Detemir ~18hr


10

Rapid-Acting Analogs and RHI in Obese Subjects

Frick AD et al. ADA 64th Scientific Sessions, 2004. Abstract 526.

0 120 240 360 480 600

Time, min

0

1

2

3

4

5

6

N=18

GlulisineLisproRegular human insulin

BMI=30 kg/m2 to 40 kg/m2

Dosage=0.3 U/kg GIR=Glucose Infusion Rate

GIR

, m

g.k

g-1.m

in-1

60

**

* p< .05 GIR-t20% vs RHI and LisproTuesday, April 11, 2023

11

Fatty Meals---Rapid Acting Insulin

TIME

INS

UL

IN A

CT

IVIT

Y

GL

UC

OS

E L

EV

EL

SHYPERGLYCEMIA


12

1. Hedman CA et al. Diabetes Care 2001;24:1120-1121 2. Home PD et al. Eur J Clin Pharm 1999;55:199-201 3. Novo Nordisk, data on file

Time (min)-60 0 60 120 180 240 300 360 420 480 540

Aspart 1,2

Pla

sma

Insu

lin

Lev

els

Effect of Premixing on Rapid-Acting Analog Properties

Tmax 49-53 min

70/30 NovoLog Mix 3Tmax 2.4 hours


13

GLUCOSEINFUSIONRATE

mg

/dl

0.3 U/Kg NPH s.c.

Plasma Glucose

908070

5.0

4.5

4.0

mm

ol/l

Lepore M. et al., Lepore M. et al., unpublished dataunpublished data

4.0

3.0

2.0

1.0

0

24

20

16

12

8

4

0

0 1 2 3 4 5 6 7 8 9Time (hours)

µm

ol/K

g/m

in

mg/

Kg/

min

PEN UP

PEN DOWN

MIX

Effect of NPH on GIR


14

Type 1 Diabetes


15

Bolus vs Basal Insulin

• Bolus insulins– Regular

– Humalog (lispro)

– NovoLog (aspart)

– Apidra (glulisine)

• Basal insulins– NPH

– Lente

– Ultralente

– Lantus (glargine)

– Levemir (detemir) Combination insulins — 70/30 and 50/50

— Humalog mix (75/25 or NPL)

— NovoLog mix (70/30 or NPA)Tuesday, April 11, 2023

16

Basic Insulin Regimen: Split-Mixed Regimen or Premix

• Does not mimic normal physiology

• Requires meal consistency

• Snacking may result in weight gain

• Hypo- and hyperglycemia

Regular

NPH

B DL HS B

Endogenous insulin

Hyperglycemia


17

Insu

lin E

ffe

ct

B DL HS

Bolus insulin

Basal insulin

Basal-Bolus or Physiologic Insulin Therapy

Endogenous insulin

Adapted with permission from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002:193


18

Case---History

25 year old student comes to clinic for management of type 1 diabetes. He was diagnosed approximately 3 years ago and has been managed with twice daily NPH insulin and lispro. He is frustrated because his glucose values fluctuate considerably, and he is having multiple episodes of hypoglycemia.

His most recent A1C returned 7.8%.


19

Case---Continuous Monitoring


20

Case Study--History

His current insulin regimen consists of 16 U of NPH plus 5 to 15 U of lispro prior to breakfast and 12 U of NPH with a similar amount of lispro prior to supper. He would give correction doses of lispro prior to lunch, bedtime and occasionally at 2-4 AM. If he was ‘low’, he would eat carbohydrate and not take lispro.

His home glucose log documented testing 4 to 5 times a day with values ranging from 40 to 500 mg/dl.

How should his management be approached? Tuesday, April 11, 2023

21

Case Study--Approach

• Set a reasonable goal for glycemic control– Initial goal was to avoid hypoglycemia (glucose

targets 120-150 mg/dL)

• Trouble-shoot the insulin regimen– Which type of insulin and which injection is

doing what? – Good luck doing it with this patient!


22


• Variables with injected insulin:– Type of insulin and site of injection– Type of food and gastric emptying– Remembering to take injections– Accuracy of HGM

• Designing an insulin regimen– Think in terms of basal and bolus


23


• We opted to use glargine as the basal insulin and lispro as the bolus insulin

• Dose calculations:– TDD: 48 to 73 U– Basal (as NPH): 16+12=28 U– Glargine: 28 x 0.8=22.4 U

CURRENT REGIMEN

16/10 and 12/10 (N/H)

TDD≈48 U/day

PLUS up to 25 U H/DTuesday, April 11, 2023

24


• Usual insulin regimens are 50:50 or 60:40 basal:bolus– TDD: 48 to 73 U– Glargine: 22 U– Bolus: ~ 22 U (50:50 Rule)

• Per meal 22/3= 7.3 U/meal

• Designed regimen: Glargine 22 U/HS; lispro 7 U BEFORE EACH MAJOR MEAL


25


• Correction doses (‘sliding scale’)– 1700 Rule (some modify this as the 1500 Rule

or the 1800 Rule)– 1700/TDD = Expected amount of glucose

lowering per unit of insulin

• Our patient– 1700/44 = 38 1 U insulin would lower his

glucose 38 mg/dl


26


• Our goal glucose is ~ 150 mg/dL• Our patient is instructed to:

– Take 22 U glargine at bed time (or ~ 10:00 PM)

– Start with 7 U of lispro before meals• For every 50 mg/dL glucose is above 150, add 1 U lispro or

for every 50 below 150, subtract 1 U lispro

– Have the patient monitor and adjust the regimen based upon results of HGM


27

Carbohydrate Counting

• There is no literature to document superiority of CHO counting– Estimation aids many patients with T1DM

– Likely not effective in T2DM

• Establishing insulin:carbohydrate ratio– [Correction factor] x 0.33 = CHO gm covered by 1 unit

of insulin

– Usual ratio is 10-15:1

– Adjust based upon 2 hour postprandial glucose values


28

Clinical Secrets

• Plan target glucose goals• Think in terms of basal and bolus insulin• Typical ratio of basal to bolus is 50:50 or 60:40• Correction doses are generally given before meals

• 1700 Rule: 1700/TDD = Glucose lowering/unit insulin

• Adjust basal insulin based upon FBS and bolus insulin based upon preprandial values


29

Summary of Key Dose Concepts for Type 1 Diabetes

Parameter Formula Usual Range

Basal insulin requirements

None (weight based 0.2-0.5

U/kg)

12-24 U/day

Bolus requirements (empiric)

Basal dose 3 or number of meals/d

5-10 U/meal

Insulin:CHO ratio CF x 0.33 ~15

Correction factor 1700 TDD 30-50

NOTE: These are approximations on starting a physiologic insulin regimen and must be adjusted based upon SMBG valuesTuesday, April 11, 2023

30

When Should Insulin Be Added In Patients With Type 2

Diabetes?


31

Natural History of Type 2 Diabetes

Adapted from International Diabetes Center (IDC). Minneapolis, Minnesota.

20 10 0 10 20 30

Years of Diabetes

Relative -Cell Function

PlasmaGlucose

Insulin resistance

Insulin secretion

126 mg/dL Fasting glucose

Postmeal glucose


32

Therapy In Type 2 Diabetes:Estimated Improvement

HbA1c FBG (mg/dL)Sulfonylurea 1.5% to 2% 50 to 60Metformin 1% to 2% 50 to 60Pioglitazone 0.6% to 1.9% 55 to 60Rosiglitazone 0.7% to 1.8% 55 to 60Glitazones (Troglit) 0.6% to 1.0% 20 to 40Repaglinide 0.8% to 1.7% 30 to 40Acarbose 0.5% to 1.0% 20 to 30Sulfonylurea + Metformin ~1.7% ~65Sulfonylurea + Pioglitazone ~1.2% ~50Sulfonylurea + Troglitazone ~0.9% to 1.8% ~40 - 60Sulfonylurea + Acarbose ~1.3% ~40Repaglinide + Metformin ~1.4% ~40Pioglitazone + Metformin ~0.7% ~40Rosiglitazone + Metformin ~0.8% ~50

Insulin TherapyOral Agents + Insulin Rx Open to Target Open to Target

Mon

oth

erap

yC

omb

inat

ion

T

her

apy


33

Evolution of Treatment Strategies

Pre-1995

Diagnosis

SU

Stop SU

Insulin

Pre-1995

Diagnosis

SU

Stop SU

Insulin

2000

Diagnosis

Monotherapy

Dual/Triple Therapy

Stop OHA

Insulin

Diagnosis

Monotherapy

Dual/Triple Therapy

Stop OHA

Insulin

2000 Current

Diagnosis

Prandial and Basal Insulin + OHA

Monotherapy Dual Therapy

Basal Insulin +

OHA

Triple Therapy

Stop SU


34

ADA/EASD Position Statement

DiagnosisDiagnosis

Lifestyle Intervention and Metformin

Lifestyle Intervention and Metformin

Check HbACheck HbA1c1c every 3 months and act until every 3 months and act until HbAHbA1c1c is <7% is <7% Nathan DM et al. Diabetes Care. 2006;29:1963-1972

HbAHbA1c1c 7%7%HbAHbA1c1c 7%7%No

Add Basal Insulin − (most

effective)

Add Basal Insulin − (most

effective)

Add Sulfonylurea −

(least expensive)

Add Sulfonylurea −

(least expensive)

Add GLitazone −( no hypoglycemia)

Add GLitazone −( no hypoglycemia)

Yes


35

How Is Insulin Employed in Type 2 Diabetes?

Different Regimens


36

B DL HS

Insu

lin E

ffe

ct

Sensitizer Basal InsulinSecretagogue

Basal Insulin Regimen


37


Regular

NPH

B DL HS B

Endogenous insulin


38

Insu

lin E

ffe

ct

B DL HS

Bolus insulin

Basal insulin

Basal-Plus Insulin Therapy

Endogenous insulin



39

Insu

lin E

ffe

ct

B DL HS

Bolus insulin

Inhaled Bolus Insulin Therapy

Endogenous insulin



40

Insu

lin E

ffe

ct

B DL HS

Bolus insulin

Basal insulin

Basal-Bolus or Physiologic Insulin Therapy

Endogenous insulin



41

How Effective Are These Regimens?


42

B DL HS

Insu

lin E

ffe

ct

Sensitizer Basal InsulinSecretagogue

Basal Insulin Therapy


43

Effects Of Basal Insulin

�□□ HS NPH+Gly+Met BID NPH

HS NPH+Metformin HS NPH+Glyburide

Yki-Järvinen et al; Ann Int Med 1999;130:389


44

*7.8

8.1

8.3

Time (wk)

0 4 8 12 16 20 24

7.5

8.0

8.5

9.0

9.5

A1

C (

%)

AM GlargineHS GlargineHS NPH

* Decrease in A1C from baseline for AM Glargine: P<0.001 vs HS NPH and P=0.008 vs HS GlargineFritsche A et al. Ann Int Med 2003;138:952-959.

Flexible Timing Of Glargine Compared With NPH Insulin


45

Treat to Target Trial

6

7

8

9

0 4 8 12 16 20 24

Mea

n A

1C (

%)

Weeks

Insulin glargine

NPH insulin

Target A1C (%)

Riddle et al. Diabetes Care. 2003;26:3080-3086

~60% of patients reached target

Subjects were oral agent failures on SU alone or

SU+metformin and basal insulin was added and aggressively titrated


46

DetemirDetemir GlargineGlargine

A1C at endpoint A1C at endpoint (baseline adjusted) (baseline adjusted)

7.16 %7.16 % 7.12%7.12%

Insulin dose at Insulin dose at endpointendpoint

0.63 u/kg (0.02-3.96)0.63 u/kg (0.02-3.96)

[0.43 u/kg (0.02-1.98) [0.43 u/kg (0.02-1.98) detemir QD (45% of pts.)]detemir QD (45% of pts.)]

[0.85 u/kg (0.14-3.96) [0.85 u/kg (0.14-3.96) detemir BID (55% of pts.)detemir BID (55% of pts.)

0.40 u/kg0.40 u/kg

Completion rateCompletion rate 80%80% 87%87%

In-clinic FPG In-clinic FPG (mg/dl)(mg/dl)

129.6129.6 129.6129.6

Rosenstock J et al. ADA 2006; Abstract 555-P

Achieving Glycemic Control (Detemir v Glargine)


47

Do Algorithms and Basal Insulin Work?

Start SU

Add metformin

Start insulin

Fanning et al. Diabetes Care 2004;27:1638-1646

Community Center + Algorithm

Community Center

Without Algorithm

University Center + Algorithm


48

Gycemia Optimization Trial

Goal FPG (mg/dl)

Glargine Dose (IU)

Proportion With A1C <

7.0%Mean

A1C (%)

Severe Hypoglycemia (Event/patient year)

A1C < 7.0% A1C ≥ 7.0%

120 (n=952) 59.2±37 31.5 7.58±1.1 0.02 0.02

110 (n=974) 62.2±37 32.2 7.52±1.1 0.02 0.08

100 (n=973) 69.6±41 37.5 7.41±1.1 0.04 0.05

90 (n=950) 74.9±53 41.1 7.26±1.1 0.08 0.12

80 (n=975) 78.1±43 44.3 7.32±1.2 0.11 0.19

Tannenberg et al. Insulin 2007;2 (suppl A):S10Tuesday, April 11, 2023

49


Regular

NPH

B DL HS B

Endogenous insulin


50

Aggressively Titrated Premix

70/30+Met+Pio Met+Pio

Baseline A1C 8.1±1.0 7.9±0.9

EOS A1C 6.5±1.0 7.8±1.2

Percentage of Patients With A1C (EOS)

<7.0% 76.3 24.1

≤6.5 59.1 11.5

≤6.0 33.3 2.3

≤5.5 14.0 0

FPG (mg/dl) 130±50 162±41

Raskin et al. Insulin 2007;2 (suppl A):S11Tuesday, April 11, 2023

51

When and How Should Prandial Insulin Be Added?


52

Contributions of FBG and PPG to Overall Glycemia

Adapted from Monnier, Lapinski, Colette: Diab Care Mar 2003, pg 881

PPG + FBG = HbA1c (%)

010203040

50607080

1 2 3 4 5

A1c Quintiles

Co

ntr

ibu

tio

n (

%)

(<7.3) (7.3-8.4) (8.5-9.2) (9.3-10.2) (>10.2)PPG

FPGTuesday, April 11, 2023

53

Insu

lin E

ffe

ct

B DL HS

Bolus insulin

Basal insulin

Basal-Plus Insulin Therapy

Endogenous insulin



54

Final Insulin Doses Basal-Plus Regimen

Abstracts of the 66th Scientific Sessions of the ADA. Abstracts of the 66th Scientific Sessions of the ADA. DiabetesDiabetes. 2006; V(suppl X): XX. Abstract XX.. 2006; V(suppl X): XX. Abstract XX.

30 31

0

5

10

15

20

25

30

35

Baseline Endpoint

Insu

lin D

ose

(IU

)

5

Baseline

11

Endpoint

Basal Insulin Dose

Rapid-Acting Dose

● 26 week study (safety analysis) (N=158)● Baseline A1C was 7.4% and fell to 7.0%● 26% achieved A1C < 6.5%


55

CHO Counting v Fixed Regimen

Mean A1C Across Study Weeks


6.5

7.0

7.5

8.0

8.5

0 2 6 12 18 24

Week

A1C

(%

) ALG

Carb Count


56

0

20

40

60

80

100

120

ALG Carb Count

P=0.04

Insulin DosesD

os

e (I

U)


110.294.3

Rapid-Acting

ALG Carb Count

Basal Insulin

103.4

86.8

P<0.0001


57

Insu

lin E

ffe

ct

B DL HS

Bolus insulin

Inhaled Bolus Insulin Therapy

Endogenous insulin



58

Inhaled Insulin (Exubera)

• Uses powdered native human insulin– 1 and 3 mg blister

packs

3mg Blister

0.15U/Kg (~10U Reg)

(3) 1mg Blister


59

Inhaled Insulin (Exubera) and OHA

*P < .001

Weiss, et al. Diabetes. 1999;48(suppl 1):A12.

10

9

8

7

5Baseline

(0)Follow-up

(12)

Oral Agents +Inhaled Insulin

Oral Agents AloneSU and/or Met

Baseline(0)

Follow-up(12)

2.3%*

Weeks

6

Hb

A1c

(%

)


60

FPG: Exubera vs SC Insulin at End Point

Hollander PA, et al. Diabetes Care. 2004;27:2356-2362.Data on file.

Exubera SCMea

n

FPG

(m

g/dL

)

-40

-35

-30

-25

-20

-15

-10

-5

0Standard Intensive

Type 2 DM

194

163

203

190

201

167

209

207

152

132

158

149

Type 1 DM

On insulin


61

What Are the Side Effects of Exogenous Insulin?


62

Hypoglycemia

Severe insulin reactions per 100 patient-yr

7.8

3

2.3

110

62

0 20 40 60 80 100 120

VA IIIP

VA CSDM

UKPDS

SDIS

DCCT Type 1 diabetes

Type 2 diabetes

Adapted with permission from McCall A. In: Leahy J, Cefalu W eds. Insulin Therapy. New York, NY:Marcel Dekker, Inc.; 2002:193


63

Total Weight Gain andTotal Insulin Dose

Adapted from Henry RR, et al. Diabetes Care. 1993;16:21-31.

0

100

200

300

400

0 10 20 30 40 50

Total insulin dose (U/d)

Total weight gain (lb)Tuesday, April 11, 2023

64

0.5

0

1

1.5

2

Weight v Delta A1C

Studies with Type 2 Diabetes

1 2 3 4

Glargine

NPH

1

14

2

2

3 3

4

2

6

5

6

5

Detemir1. Yki-Jarvinen Diabetes Care 2000;23:1131 2. Rosenstock Diabetes Care 2001;24:631 3. Riddle Diabetes Care 2003;26: 3079 4. Fritsche Ann Int Med 2003;138: 952 5.Raslova Diab Res Clin Pract 2004;66:193 6. Haak Diab Obes Clin Pract 2005;7:56 R

educ

tion

in A

1C (

%)

Weight Gain (kg)

7. Study 1530 8. Study 1337 9. Study 1373; Rosenstock, 2006

77

8

8 99


65

How Do The Various Approaches Compare?


66

Comparison of Common Insulin Regimens*

Variable Glargine* NPH1 Premix2,3 Detemir4

Efficacy Insulin Works

Hypoglycemia† 1.0 1.4X 2.5-5.0X 1.0

Insulin Dose 1.0 1.0 1.5-2.0X 1.6-2.1X

Weight Gain 1.0 1.0 1.5X 0.7-1.0X

*Normalized to glargine; sponsored comparator trials †Confirmed hypoglycemia1Riddle MC et al. Diabetes Care 2003;26:3080-3086 2Janka HU et al. Diabetes Care 2005;28:254-259 3Raskin P et al. Diabetes Care 2005;28:260-265 4Rosenstock J et al. ADA 2006; Abstract 555-P


67

Conclusions

• Adjunctive therapy with insulin in type 2 diabetes is both safe and effective

• Instead of being the ‘last resort’, early insulin use is being encouraged by national organizations

• Choice of insulin and/or regimen is dependent upon:– The patient

– Pre-existing glycemic control

– Duration of illness


68

insulin regimens

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