Insulin Lispro Revisited

Insulin Lispro
Usama Ragab Youssif, MD
Consultant Internal Medicine
Lecturer of Medicine
Zagazig University
Email: usamaragab@medicine.zu.edu.eg
Slideshare: https://www.slideshare.net/dr4spring/
Mobile: 00201000035863

History
• The discovery of insulin was one of the
most dramatic and important milestones
in medicine - a Nobel Prize-winning
moment in science.

Paul Langerhans, a medical
student in Berlin, discovers a
distinct collection of cells
within the pancreas. These
cells would later be called the
Islets of Langerhans.
Paul Langerhans had discovered the beta cell
1869
Langerhans, P. (1869). Beitrage zur mikroskopischen Anatomie der Bauchspeicheldruse, Inaugural Disseration. Gustav Lange.
Langerhans, P., & Morrison, H. (1869). Contributions to the microscopic anatomy of the pancreas. Johns Hopkins Press.

In 1889, two German
researchers Oskar Minkowski
and Joseph von Mering
discovered that removing a
dog’s pancreas would provoke
severe symptoms of diabetes.
Pancrease is essential for LIFE
1889
Karamanou, M., et al. (2016). Milestones in the history of diabetes mellitus: The main contributors. World journal of diabetes, 7(1), 1.

Romanian professor Nicolae Paulescu
develops an extract of the pancreas
and shows that it lowers blood sugar
in diabetic dogs.
First trial in animals
1916
Karamitsos, D. T. (2011). The story of insulin discovery. Diabetes research and clinical practice, 93, S2-S8.

The Discovery
1922
• Frederick Banting had the idea that
began the discovery process. He
performed the surgeries on the dogs.
The discovery of insulin was the highlight
of his career.
• Charles Best, a young biochemistry
student, assisted Banting.

The first human with
diabetes to receive insulin
was Joseph Gilchrist.
First Patient
https://www.nytimes.com/1982/09/14/science/the-tumultuous-discovery-of-insulin-finally-hidden-story-is-
told.html

The first injection of insulin
was given to fourteen-year-
old Leonard Thompson, who
had been diagnosed in 1919.
First Patient
Jan 1922

Banting and Best improve
their techniques for the
production of insulin and Eli
Lilly becomes the first insulin
manufacturer.
Nobel Prize

The duration of action was short about 3 to 6 hours

NPH
• Danish physician Hans Christian
Hagedorn discovers the action of insulin
can be prolonged with the addition of
protamine (1936) to form microscopic
clumps.
• NPH, an intermediate acting insulin, is
marketed by Danish pharmaceutical
company Novo Nordisk (1950).

Insulin
Manufacturing
• Lilly is the world's largest
producer of insulin; Novo is
second.

Insulin is sequenced by British biochemist Frederick Sanger,
and is the first protein to be fully sequenced.
In 1958 Sanger receives the Nobel Prize in Chemistry for his r
esearch.
Another Nobel Prize

Different Forms of Insulin
The available Insulin nowadays
1- Human Insulin.
2- Insulin Analogues.
3- Biosimilars.

Human Insulin
Short Acting Insulin
Regular Insulin
Premixed Insulin
NPH/Regular insulin
Intermediate Acting
NPH

PERSONAL USE ONLY
Serum
Insulin
Level
Time
Analogue Bolus
Human Basal
Analogue Basal
Human Bolus
guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca

Different Forms of Insulin
1- Human Insulin.
2- Insulin Analogues.
3- Biosimilars.

Serum
Insulin
Level
Time
Analogue Bolus
Human Basal
Analogue Basal
Human Bolus
guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca

Insulin Analogues
Rapid Acting Analogues
1- Insulin lispro (Humalog)
2- Insulin aspart
3- Insulin glulisine
Long Acting Analogues
1- Insulin glargine (U100 and U300)
2- Insulin detemir
3- Insulin Degludec (U100 and U200)
Premixed Analogues
1- Insulin lispro/lispro protamine (Humalog mix)
2- Insulin aspart/aspart protamine
3- Insulin Lispro/degludec = coformulation

Mane, Krishnappa, et al. "Review of insulin and its analogues in diabetes mellitus." Journal of basic and clinical pharmacy 3.2 (2012): 283.

Insulin Lispro
Proline lysine substitution B28-B29.
The first genetically engineered rapid-acting insulin analogue (1996)
There’s decreased tendency for self-association and as a result faster
absorption, higher peak serum levels and shorter duration of action
Rapid On and Off

What is the difference between Humalog
u100 and u200 insulin?
U-100 means there are
100 units of insulin in
every 1 mL. U-200 means
there are 200 units of
insulin in every 1 mL.
Humalog U-200 is only
available as an insulin
pen.

No dosing conversion required
Humalog U200 is
BIOEQUIVELENT
to Humalog U100
So
Same Units in Less Volume
One Pen Remains Longer
So

Improved glide force
compared to insulin l
ispro 100 units/ml pr
efilled pen
Humalog U200 Units/ml Prefilled Pen:
Device Overview
Humalog [SmPC]. Houten, The Netherlands: Eli Lilly and Company, 2015
Rees TM et al. J Diabetes Sci Technol 2015;9:316-9
Contains 600 units vs. 300 units in the same 3-ml pen
Insulin lispro 200 units/ml allows the same dose to be
administered in 1/2 the volume of insulin lispro 100 uni
ts/ml
User interface (dialing by single units up to 60) re
mains unchanged and no dose conversion needed
from the current 100 units/ml prefilled pen

Insulin Lispro 200 Units/ml Prefilled Pen:
Rees TM et al. J Diabetes Sci Technol 2015;9:316-9
Contains 600 units vs. 300 units in the same 3-ml pen
Insulin lispro 200 units/ml allows the same dose to be a
dministered in 1/2 the volume of insulin lispro 100 unit
s/ml
1)

♦ 60 unit maximum single dose
♦ 600 units in 1 pen
♦ Dials and doses in single unit
increments
♦ For example - 40 unit dose:
• Dial to 40 units
• Same thumb reach
• 0.2 ml (half the volume)
♦ 60 unit maximum single dose
♦ 300 units in 1 pen
♦ Dials and doses in single unit
increments
♦ For example - 40 unit dose:
• Dial to 40 units
• Same thumb reach
• 0.4 ml
Insulin Lispro 100 Units/ml vs. 200 Units/ml Prefilled Pen
Identical dosing if a patient receives a 100 units/ml a 200 units/ml pen
Humalog U200 pen
Humalog U100 pen

Humalog 200U
Insulin Lispro 10
0 Units/ml
Insulin Lispro 20
0 Units/ml
Glucose
Infusion
Rate
(mg/min)
de la Peña A et al. Clin Pharmacol Drug Dev 2016;5:69-75

Position of
Insulin in
diabetes

Pharmacologic Therapy For Adults With Type 1
Diabetes
Diabetes Care 2023;46(Suppl. 1):S140–S157

Copyright ADA/EASD 2022
Putting the Person with Diabetes at the Centre of Care
DaviesMJ,ArodaVR,CollinsBS,GabbayRA,GreenJ,MaruthurNM,RosasSE,DelPratoS,MathieuC,MingroneG,RossingP,TankovaT,TsapasA,BuseJB
DiabetesCare2022;https://doi.org/10.2337/dci22-0034.Diabetologia2022;https://doi.org/10.1007/s00125-022-05787-2.

Diabetes Care 2
023;46(Suppl. 1
):S140–S157

Type 2 diabetes is a progressive disease
By time the endogenous insulin is lost and full
insulin replacement is required
OAD: Oral anti diabetics.
Schematic representation Adapted from Raccah et al. Diabetes Metab Res Rev 2007; 23: 257–264

Insulin
• Advantage of lowering glucose in dose-
dependent manner, able to address any level
of glycaemia
• Clinical Profile: High to very high glycaemic
efficacy
• Increased risk of hypoglycemia and weight
gain; neutral cardiorenal profile
• Importance of matching insulin to physiologic
need
Adapted from Hirsch I et al; Endocr Rev 2020; 41: 733-755

Intensification Options
After Basal Insulin
• Add an OAD
• Add a short-acting insulin at
mealtime
• Switch to premixed insulins
• Novel insulin combinations
• Basal insulin/GLP-1 RA
combinations

Why Does Intensification of Insulin Therapy Not Happen in Many Patients
With T2DM?
• Physician barriers
• Inexperience with using insulin; lack of resources/training
• Fear of hypoglycemia
• Not buying into HbA1c targets; don’t want to be too aggressive
• Patient barriers
• Insulin carries “baggage” (eg, negative family experience, “end of the
road” perception)
• Educational issues about insulin dose increases
Clinical inertia
Progressive nature of disease

When
Too early is better than too late

Clinical Inertia
Clinical inertia: failure of healthcare providers to initiate or
intensify therapy when indicated, due to:
• overestimation of care provided
• use of “soft” reasons to avoid intensification of therapy
• lack of education, training, and practice organisation
aimed at achieving therapeutic goals
.

Treat to Failure
Traditional stepwise approach versus early intervention approach to diabetes management, adapted from Del Prato S, et al.
A stepwise approach often leads to unacceptable delays in achieving and maintaining glycemic goals. An early intervention approach can be considered a ‘proactive’ approach versus the
‘reactive’ stepwise approach and is suggested to provide better and more rapid glycemic control. OAD, oral antidiabetic drug.
1. Khunti K, et al. Prim Care Diabetes 2017;11:3–12; 2. Khunti K, et al. Diabetes Care 2013;36:3411‒7; 3. Del Prato S, et al. Int J Clin Pract. 2005;59:1345–55.
Early intervention approach
(conceptual data)
10
HbA
1c
%
9
8
7
6
2.9 years 7.2 years
6.7 years
Time
8.5%
OAD
monotherapy
9.7%
Insulin
8.7%
OAD dual
combination
9.1%
OAD triple
combination
Traditional stepwise
treatment approach
(actual data)

When basal insulin is not enough1
PPG excursion should be addressed with another agent if insulin dose reached
~0.5 U/kg/d without enough control
U/Kg/D: International unit or unit per Kilogram per day, FPG: fasting plasm glucose
Standards of Medical Care in Diabetes - 2023. Diabetes Care 2023;46(Suppl. 1):S140–S157
ADA 2023: “Evaluate for overbasalization”
to further individualize therapy
Reconsider injectable therapies strategy
when reaching 0.5 U/Kg/Day of basal insulin
Overbasalization

Pharmacologic Therapy for Type 2 Diabetes
(continued)
Pharmacologic Approaches to Glycemic Treatment
9.13 Medication regimen and medication- taking behavior should be
reevaluated at regular intervals (every 3–6 months) and adjusted as
needed to incorporate specific factors that impact choice of treatment
(Fig. 4.1 and Table 9.2). E
9.14 Clinicians should be aware of the potential for overbasalization with
insulin therapy. Clinical signals that may prompt evaluation of
overbasalization include basal dose more than 0.5 IU/kg/day, high
bedtime-morning or postpreprandial glucose differential, hypoglycemia (aware
or unaware), and
high glycemic variability. Indication of overbasalization should prompt
reevaluation to further individualize therapy. E

Bedtime-to-Morning
Glucose Difference
• A difference of ≥ 50-55 mg/dL
between bedtime and
morning glucose (BeAM)
values in patients with type 2
diabetes (T2D) on basal
insulin is an indicator of poor
postprandial glucose control.

When to consider prandial option
If basal titrated
to acceptable
FPG and A1c is
still elevated
If basal dose exceed
0.5 unit/kg/day
a. ADA. Diabetes Care. 2018;40:S73-S85; b. Garber Al, et al. Endocr Pract. 2017;23:207-238.

Of course, we fix fasting first “FFF” But…
Low/Normal
FPG
Glycemic
Control

PPG contributes significantly to overall hyperglycemia in lower A1c
FPG, fasting plasma glucose; PPG, postprandial plasma glucose
Adapted from Monnier. Diabetes Care 2003;26(3):881–5

Maximum basal does NOT mean better control
Limited/no more A1c
reduction
More hypoglycemia
More weight
gain
Less Adherence
Poor Control
a. ADA. Diabetes Care. 2018;40:S73-S85; b. Garber Al, et al. Endocr Pract. 2017;23:207-238.

Indications for
Initiating Insulin
Therapy in T2DM
Adjunctive therapy:
• When oral therapy fails to achieve targets
Replacement therapy:
• when both basal & meal-time insulin are needed
Glucotoxicity, and triggers for tarting insulin:
• Persistent hyperglycemia > 250 mg/dl
• HbA1c > 10%
• Ketonemia & Ketonuria
• Persistent symptoms and weight loss
Contraindications to OADs:
• Severe liver or renal disease

Options
Diabetes Care 2023;46(Suppl. 1):S140–S157

Sequential
Insulin
Strategies In
T2DM

Intensifying to injectable therapies in type 2 diabetes

Prandial insulin titration
• Can usually begin with ~4 units, (0.1
U/kg or 10% basal dose) before the
main meal.
• Adjust by 1 – 2 units every 3 days until
post prandial plasma glucose is in
desired target range.
Nathan DM, et al. Diabetes Care 2009;32 193-203.

Intensifying to injectable therapies in type 2 diabetes (cont.)

Discussing Prandial
Therapy with
patients
• Contraindications
• PPG monitoring
• I shall eat everything
• Side effects
• Injections
• Insurance
• My Weight
• A lot of WhatsApp messages
Don’t Forget
Insulin = Titration

ADA/EASD 2018 Consensus Report
DPP-4i
Stop DPP-4i if GLP-1
RA initiated
SU
If on SU stop or reduc
e dose by 50% when
basal insulin initiated
TZD
Stop TZD when
commencing ins
ulin OR reduce d
ose3
If on SGLT-2i continue
treatment
Consider adding SGLT-
2i if:
• Established CVD
• If HbA1c above targe
t or as weight reduct
ion aid
Metformin
Continue treatment
with Metformin
Use of concomitant oral therapy when intensifyin
g to injectables
Metformin
Continue treatment
with metformin
SGLT-2i
If on SGLT-2i, continue t
reatment.
Consider adding SGLT-2i
if:
• Established CVD
• If HbA1c is above target or
as weight reduction aid
TZD
Stop TZD when
commencing ins
ulin OR reduce d
ose
SU
If on SU, stop or redu
ce dose by 50% when
basal insulin
is initiated
DPP-4i
Stop DPP-4i if
GLP-1RA is initiated
Beware:
• DKA (euglycaemia)
• Instruct on sick-day rule
s
• Do not down-titrate insul
in over-aggressively
Consider stopping SU if pra
ndial insulin initiated or on
a premix regimen
DPP-4i
Go on DPP-4i if
Insulin is initiated

Why lispro is more convenient?
Human Insulin Lispro
• Slower onset of activity that requires
injections to be given 30 to 45 minutes
before meals.
• Safety concerns if the meal is not eaten
when scheduled leads to
Hypoglycemia.
• A prolonged duration of action (up to 12
hours of activity): Risk of hyper-
insulinemia
Using a rapid-acting insulin analogue for patients with
pediatric diabetes may provide a therapeutic alternative to:
• Postprandial hyperglycemia
• Nocturnal hypoglycemia
• Problems injecting insulin 30 minutes before meals
• Desire for flexibility in food intake/timing
 Meal size, timing
 Snacks (desired, undesired), large snacks
compromising intermeal glucose control
 Amounts eaten are variable or difficult to predict
• Insulin timing, dose with activity: Scheduled and
unscheduled activity

Significant reduction in Postprandial Blood Glucose Excursions with
Lispro® vs Human Insulin®
Anderson JH et al. Arch Internal Med 1997;157:1249-1255.
6-month crossover study: mealtime Lispro or regular human insuli
n for 3 months, then switch to other treatment
Regular Insulin
Lispro
*p<0.001
Postprandial time (h)
Rise
in
Serum
Glucose
(mmol/L)
*
N = 722 type 2 diabetes
*
0
1
2
3
4
0 1 2
53 %

lower risk of Overall and Nocturnal Hypoglycemia with Lispro VS
Regular Human Insulin
Combined treatment periods (episodes/patient/30 days)
Anderson JH et al. Arch Internal Med 1997;157:1249-1255.
All Episodes (overall) Episodes from Midnight to 6AM
P=0.02
P<0.001
0.
0.2
0.4
0.6
0.8
1.0
0
1
2
3
4
Regular Insulin
Lispro
36 %
Hypoglycemia
rate

Why choose
the stepwise
basal-bolus
intensification
approach
Irregular meal-
times & lifestyle
of patient
Higher education
level and able to
institute multiple
injections
Achieve tighter
glycemic control
More advance
disease or
duration of
diabetes

Recommended Steps for the
Intensification of Insulin Therapy
When Prandial Control Is Needed

Postprandial
hyperglycemia
• When control of postprandial hyperglycemia is needed and
a basal insulin and a GLP-1 RA are already being used,
preference should be given to rapid-acting insulins (the
analogs lispro, aspart, and glulisine or the rapid-acting
inhaled human insulin powder) over regular human insulin.
The former have a more consistent and a more rapid onset
and offset of action with less risk of hypoglycemia. Grade A;
BEL 1

Pregnancy
• Rapid-acting insulin analogs (insulin-lispro, insulin-
aspart) should be used to treat postprandial
hyperglycemia in pregnant women. Grade B; BEL 1

Different stages of insulin therapy in type 2 diabetes
• Starting insulin therapy (usually with
basal oral therapy)
• Dose titration to ensure that the
patient receives the maximum benefit
from the prescribed treatment
• Modification of an insulin regimen
e.g. adding of another type of insulin
to maintain glycaemic control
INTENSIFY
Titrate
INITIATE

Step Two: Intensifying Insulin
• If fasting blood glucose levels are in target range but HbA1c ≥7%, check
blood glucose before lunch, dinner, and bed and add a second injection:
 If pre-lunch blood glucose is out of range,
 add rapid-acting insulin at breakfast
 If pre-dinner blood glucose is out of range,
 add rapid-acting insulin at lunch
 If pre-bed blood glucose is out of range,
 add rapid-acting insulin at dinner
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

Making Adjustments
Can usually begin with ~4 units and
adjust by 2 units every 3 days until
blood glucose is in range
When number of insulin Injections
increase from 1 to 2 Stop or taper
of insulin secretagogues (SU).

Step Three:
Further Intensifying Insulin
Recheck pre-meal blood glucose and if out of
range, may need to add a third injection
If HbA1c is still ≥ 7%
• Check 2-hr postprandial levels
• Adjust preprandial rapid-acting insulin

Final Bottom line
Insulin is essential for life
-Insulin has changed the practice of diabetes since it’s introduction i
n 1922.
-Insulin has a wide metabolic activities.
-Insulin has different preparation, you can use them in different
ways according to profile of your patient (One Size Doesn’t Fit All).
-Thanks Banting for Insulin.

I just adore Toronto and Dr. Banting!
-Elizabeth Hughes “one of the first patients of Banting”,
letter to her mother, 1922
Thanks
Cooper T, Ainsberg A. Breakthrough: Elizabeth Hughes, the Discovery of Insulin, and the Making of a Medical Miracle. New York: St Martin’s Press; 2010.

Company Confidential / EVA Pharma-
Humalog portfolio price list
Product Humalog 200u
Kwikpen
Humalog 100u
Kwikpen
Humalog 100u
Cartridge
Humalog Mix 50
Kwikpen
Humalog Mix 25
Kwikpen
Unit price 207 128.8 105.8 137.4 137.4

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