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
• 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)
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
• 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)
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
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)
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
Time of administration
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.
Basal insulin
Time of administration
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
Time of administration
Basal Plus Bolus (main meal)
Bolus Insulin
Basal Insulin
Basal-plus will affect …
Breakfast Lunch Supper
Before After Before After Before After Bedtime
Sunday
Monday
Tuesday
Wednesday
Thursday
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.
Basal-Bolus Insulin
Time of administration
Basal-bolus will affect …
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
• Basal Plus or Basal-Bolus (cont met)
– Meal-time insulin added at largest meal (or breakfast)
– Multiple daily injections (meal-time + basal)
– Pros and cons
• Premixed (continue metformin)
– Premixed at one or more meals
B DL HS
Ins
ulin
eff
ec
t
Endogenous Insulin
Time of administration
BID Premixed
If on premixed …
Breakfast Lunch Supper
Before After Before After Before After Bedtime
Sunday
Monday
Tuesday
Wednesday
Thursday
Reflects the bolus portion of the premixed
injection at breakfast / dinner
If on premixed…
Breakfast Lunch Supper
Before After Before After Before After Bedtime
Sunday
Monday
Tuesday
Wednesday
Thursday
Reflects the intermediate portion of the
premixed injected the night before /
breakfast
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
• 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
– 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
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