INSULIN 101: When, How and What - Amazon S3 · (Lantus) • SEB glargine 100 u/mL (Basaglar) • Degludec (Tresiba) • Glargine 300 u/mL ... Adapted from Raccah D. et al. Diabetes/Met

INSULIN 101:

When, How and What

Alice YY Cheng

@AliceYYCheng

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Faculty/Presenter Disclosure

• Alice Cheng

Relationships with commercial interests:– Grants/Research Support/Clinical Trials:

• Amgen, Sanofi, Eli Lilly, Pfizer, Novo Nordisk

– Speakers Honoraria:• Abbott, AZ, BD, BI, BMS, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi, Valeant

– Consulting Fees: • Abbott, AZ, BI, BMS, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi, Servier,

Valeant

– Other:

Learning objectives

By the end of this session, you will be able to:

1.Recognize when to initiate insulin

2.Discuss the 3 insulin types and regimens

3.Understand how to dose and titrate insulin

When should insulin be

started in type 2 diabetes?

1. Max non-insulin agents but A1c > 7%

2. New diagnosis > 8.5%

3. Metabolic decompensation

4. End-organ failure

5. Pre and during pregnancy

6. Acute illness / Drugs

7. Whenever you feel like it!

InsulinAll options

open

COULD THE PATIENT BE INSULIN DEFICIENT?

• Lower BMI

• Lack of glycemic

lowering with other meds

• Duration of T2DM

(sometimes)

• Higher BMI

• Shorter duration of

T2DM (sometimes)

Consider the core defect!Insulin is REPLACEMENT therapy

Why don’t we use more?

How to choose type and

regimen?

“The Rule of 3’s”

3 Types of insulins

BASAL• NPH

• Detemir (Levemir)

• Glargine 100 u/mL (Lantus)

• SEB glargine 100 u/mL (Basaglar)

• Degludec (Tresiba)

• Glargine 300 u/mL(Toujeo)

PRE-MIXED

• 30/70

• Insulin lispro/lispro protamine (Humalog Mix25, Mix50)

• Biphasic insulin aspart (Novomix 30)

BOLUS

• Regular (R or Toronto)

• Aspart (Novorapid)

• Glulisine (Apidra)

• Lispro (Humalog)

• Lispro 200 u/mL (Humalog)

• Faster aspart (Fiasp)

3 Types of insulins

BASAL• NPH






PRE-MIXED

• 30/70



BOLUS







McMahon GT, Dluhy RG. NEJM 2007;357:1759.

0 12 24

Rela

tive G

lycem

ic E

ffect

Duration in Hours

NPH

Detemir

Glargine

Time-action profile of basal insulins

Basal insulin therapy: The next generation

Gla-300, insulin glargine 300 U/mL; IDeg, insulin degludec

degludecGla-300

2015 2017

Time, h

3

2

1

0

7.8

6.7

5.5

8.9

0 6 12 18 24 30 36

Glargine 300 U/mL: Next Generation1/3 volume, flatter and longer PK/PD

U300 0.4 U/kg

U100 0.4 U/kg

0 6 12 18 24 30 36

Glucose infusion rate, mg/kg/min

Blood glucose, mmol/L

Becker RHA et al. Diabetes Care. 2014; Published ahead of print: doi: 10.2337/dc14-0006

Euglycemic clamp study in patients with T1D after 8 days’ treatment

PD, pharmacodynamic; PK, pharmacokinetic

Reduction of volume by 2/3

100 U/mL

(U100)

300 U/mL

(U300)

300 U/mL

(U300)100 U/mL

(U100)

Reduction of depot surface by 1/2

Gla-300: Percentage of participants (T2DM) reporting ≥1 hypoglycemic event at any time (24 hours)

Ritzel R, et al. Diab Obes Metab 2015; 17:859-67. † Significant

0

20

40

60

80

100 Relative risk 0.91(95% CI 0.87, 0.96)†

Relative risk 0.83(95% CI 0.77, 0.89)†

54.1

Relative risk 0.92(95% CI 0.86, 0.98)†

Entire treatment period(Baseline to Month 6)

Titration period(Baseline to Week 8)

Maintenance period(Week 9 to Month 6)

Gla-100 (n = 1246)

Gla-300 (n = 1242)

72.065.5

44.7

62.557.5

Participants with ≥1 confirmed (≤3.9 mmol/L) and/or severe hypoglycemia, %

From pooled T2D population across entire treatment period:• For every 15 subjects initiated and treated with Gla-300 instead of Gla-100,

1 less patient will have confirmed hypoglycemia at any time (24 hours)

Par

tici

pan

ts, %

Clinical Implications

1. Owens DR, et al. Diabetes Metab Res Rev. 2014;30:104–19

2. Shah VN, et al. Diabetes Technol & Ther. 2013;15:727–32

3. Heise T , et al. Diabetes Obes Metab 2012;14:944–50

Upon

subcutaneous injection

forms soluble and

stable multihexamers,

that allow slow and

continuous absorption

of monomers into

the circulation1,2

0 4 8 12 16 20 24

0.8 U/kg

0.6 U/kg

0.4 U/kg

5

4

3

2

0

1

Glu

co

se

In

fusio

n R

ate

in

T1

DM

pa

tie

nts

at

Da

y 6

, m

g/k

g/m

in

Hours

▪ A half-life of ~25 hours, and is detectable

in serum for >120 hours post-injection2

Insulin Degludec: Next GenerationFlatter and longer PK/PD

IDeg: Overall hypoglycemia rates vs. Gla-100Meta-analysis of Phase IIIa trials in overall T2DM population

Ratner RE, et al. Diab Obes Metab. 2013;15:175–84

*Significant

RR, rate ratio

-30

-25

-20

-15

-10

-5

0

Entire treatment period Titration period Maintenance period

OVERALL confirmed (BG <3.1 mmol/L) or severe hypoglycemia

Estim

ate

d R

R r

ed

uctio

n

RR: 0.83 *

(0.74–0.94)

RR: 0.92

(0.80–1.05)

RR: 0.75 *

(0.66–0.87)

Clinical

Implications

From pooled overall T2DM population across entire treatment period:

• For every 3 subjects initiated and treated with degludec instead of

Gla-100 for 1 year, 1 overall confirmed episode will be avoided

(Baseline to 26 or 52 weeks) (Baseline to 15 weeks) (16 weeks onwards)

3 Types of insulins

BASAL

• NPH






PRE-MIXED

• 30/70



BOLUS







McMahon GT, Dluhy RG. NEJM 2007;357:1759.

0 12 24

Rela

tive G

lycem

ic E

ffect

Duration in Hours

Human Regular

Aspart

Glulisine

Lispro

Faster‐acting insulin aspart: Earlier onset of appearance and greater early pharmacokinetic and

pharmacodynamic effects than insulin aspart

Diabetes, Obesity and MetabolismVolume 17, Issue 7, pages 682-688, 8 MAY 2015 DOI: 10.1111/dom.12468http://onlinelibrary.wiley.com/doi/10.1111/dom.12468/full#dom12468-fig-0001

http://onlinelibrary.wiley.com/doi/10.1111/dom.2015.17.issue-7/issuetoc

http://onlinelibrary.wiley.com/doi/10.1111/dom.12468/full#dom12468-fig-0001

3 Types of insulins

BASAL

NPH

Detemir (Levemir)

Glargine 100 u/mL (Lantus)

SEB glargine 100 u/mL (Basaglar)

Degludec (Tresiba)

Glargine 300 u/mL(Toujeo)

PRE-MIXED

• 30/70



BOLUS







B DL HS

Ins

ulin

eff

ec

t

Time of administration

Premixed

Premixed analogue

Premixed human

Humulin or Novolin

30/70

Humalog Mix25, Mix50Novomix 30

3 Insulin Regimens

B DL HS

Ins

ulin

eff

ec

t Bolus Insulin

Basal Insulin

Endogenous Insulin

B = breakfast; L = lunch; D = dinner; HS = bedtime.

1. Leahy JL. In: Leahy JL, Cefalu WT (eds). Insulin Therapy. Marcel Dekker Inc., New York, 2002.

2. Bolli GB, et al. Diabetologia 1999; 42:1151-67.

Normal Insulin Secretion:

The Basal-Bolus Insulin Concept


B DL HS

Ins

ulin

eff

ec

t Bolus Insulin

Basal Insulin

Endogenous Insulin




Basal insulin


Basal insulin affects …

Breakfast Lunch Supper

Before After Before After Before After Bedtime

Sunday

Monday

Tuesday

Wednesday

Thursday

Type 2 Diabetes Insulin Options

• Basal (continue all oral agents)

– NPH at bedtime

– Glargine once daily at any time of the day

– Detemir once daily at any time of the day

– Pros and cons

• Basal Plus or Basal-Bolus

– Meal-time insulin added at largest meal (or breakfast)

– Multiple daily injections (meal-time + basal)

• Premixed (continue metformin)

– Premixed at one or more meals

B DL HS

Ins

ulin

eff

ec

t

Endogenous Insulin


Basal Plus Bolus (main meal)

Bolus Insulin

Basal Insulin

Basal-plus will affect …



Sunday

Monday

Tuesday

Wednesday

Thursday

B DL HS

Ins

ulin

eff

ec

t Bolus Insulin

Basal Insulin

Endogenous Insulin




Basal-Bolus Insulin


Basal-bolus will affect …



Sunday

Monday

Tuesday

Wednesday

Thursday



– NPH at bedtime



• Basal Plus or Basal-Bolus (cont met)



– Pros and cons



B DL HS

Ins

ulin

eff

ec

t

Endogenous Insulin


BID Premixed

If on premixed …



Sunday

Monday

Tuesday

Wednesday

Thursday

Reflects the bolus portion of the premixed

injection at breakfast / dinner

If on premixed…



Sunday

Monday

Tuesday

Wednesday

Thursday

Reflects the intermediate portion of the

premixed injected the night before /

breakfast



– NPH at bedtime



• Basal Plus or Basal-Bolus





– Pros and cons

How do the regimens compare?

• Basal start has advantages (4T)

• Diabetes is PROGRESSIVE

• The regimen must change over time

• All roads lead to Basal Bolus concept

• If you’re not going to TITRATE – don’t start

Intensification of Therapy in T2DM

Progressive deterioration of -cell function

Lifestyle changes

OHA monotherapy and combinations

BasalAdd basal insulin and titrate

Basal PlusAdd bolus insulin at main meal

A1C above target

FBG above target

A1C above target

Basal bolusAdditional prandial doses as needed

FBG at target

A1C above target

OHA=oral hypoglycaemic agent

Adapted from Raccah D. et al. Diabetes/Met Res & Rev 2007;23:257-64.

Intensification of Therapy in T2DM

Progressive deterioration of -cell function

Lifestyle changes

OHA monotherapy and combinations

BasalAdd basal insulin and titrate

Basal PlusAdd bolus insulin at main meal

A1C above target

FBG above target

A1C above target

Basal bolusAdditional bolus doses as needed

FBG at target

A1C above target

OHA=oral hypoglycaemic agent

Adapted from Raccah D. et al. Diabetes/Met Res & Rev 2007;23:257-64.

How to dose?

“Whatever you pick will be

WRONG … and that’s okay!”

• You will inject ______ units of insulin each night

• You will continue to increase by 1 unit every night until your

blood sugar level is _______ mmol/L before breakfast

• Do not increase your insulin when your fasting blood sugar is

_______ mmol/L

Basal insulin self-titration tool

10

4-7

4-7

Basal Plus or Basal-bolus

• If full Basal-Bolus: 0.5 u/kg = TDI

• 50% bolus, 50% basal (or 60:40)

OR

• Add 10% of basal dose as bolus insulin ac meal (4T-study)

OR

• Add 2 units of bolus insulin at a meal and self-titrate (START protocol)

OR

• Add 4 units of bolus insulin at a meal and self-titrate (STEPwise protocols)

Premixed

• 0.5 units / kg = TDI

• 1/2 in the AM + 1/2 in the PM

OR

• 5-10 units BID

What about the orals?

• METFORMIN

• METFORMIN

• Secretagogues if basal alone

• TZD – stop

• DPP-4 – benefit but cost

• GLP-1 receptor agonist – benefit (dose & weight) but cost

• SGLT2 inhibitor – benefit but cost

How can I remember??

DOSING

SEE REVERSE FOR TIPS

CHOOSE AN

INSULIN TYPECHOOSE A

BRAND

SELECT PEN

DEVICECHECK OFF

SUPPLIES

QUANTITY &

REPEATS

SIGN AND DATE

guidelines.diabetes.ca/BloodGlucoseLowering/Insulin

PrescriptionTool

http://guidelines.diabetes.ca/BloodGlucoseLowering/InsulinPrescriptionTool

Summary

• 3 types of insulin

• 3 generations of insulin

• 3 types of regimens

• Pick a starting dose – it will be wrong –

just be sure to titrate

• Change over time ….

@AliceYYCheng

Documents

INSULIN 101: When, How and What - Amazon S3 · (Lantus) • SEB glargine 100 u/mL (Basaglar) • Degludec (Tresiba) • Glargine 300 u/mL ... Adapted from Raccah D. et al. Diabetes/Met