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The Art and Science of Insulin
Role of Modern Basal/Prandial Insulins
inType 2DM
Mesbah Sayed Kamel
MD
Disclosures
• I have provided services ( speaker, advisor, consultant
and investigator in clinical trials ) for the following
companies:
Novo Nordisk, MSD,Sanofi Aventis, Novartis
,Lilly,Astra Zenica&Merck Sorono.
• For these activities I received appropriate honoraria
and/or grant support.
2
Clinical Challenge
Person with Type 2 Diabetes on Oral Therapies but HbA1c Is 9.4%*
Case Presentation:
 Age: 52 years
 Duration of type 2 diabetes: 7 years
 Review of patient logbook shows FPG of
9.9-16.3 mmol/L (178.2-293.4 mg/dL) over
the past 2 months
 Weight: 209 lbs (95 kg)
 BMI: 31.8 kg/m2
 Blood pressure: 135/85 mmHg
 Current treatment: glipizide 10 mg QD,
metformin 1000 mg BID
 No reported hypoglycaemia
Lab Results:
 FPG: 10.4 mmol/L (187.2 mg/dL)
 2-hour PPG: 14.7 mmol/L (264.6 mg/dL)
 Total cholesterol: 4.7 mmol/L
(181.5 mg/dL)
 Triglycerides: 1.9 mmol/L (168.1 mg/dL)
 AST: 15 IU/L
 ALT: 19 IU/L
 HbA1c: 9.4%
 Urine microalbumin: 18 mg/24 hr
What therapeutic decisions would you make to
help this patient reach his or her HbA1c goal?
*Hypothetical patient case.
ALT = alanine transaminase; AST = aspartate transaminase; BID = two times per day; BMI = body mass index; FPG = fasting
plasma glucose; PPG = postprandial plasma glucose; QD = once per day.
Patient Perspective:
 Wants to improve glycaemic control and is willing to add an injectable therapy
…but wants to minimise the number of injections
 Has a fairly predictable daily routine, including meal composition
ARS = audience response system; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; TZD = thiazolidinedione.
ARS Question
What would be the next step in therapy for this patient?
a) No change to therapy – monitor HbA1c again in 3 months
b) Add an additional oral agent (eg, TZD, DPP-4 inhibitor)
c) Add a basal insulin at bedtime
d) Stop glipizide, begin a premixed insulin analogue therapy
e) Stop orals and start basal/bolus insulin therapy
f) Add a GLP-1 receptor agonist
UKPDS
A 1% Decrease in HbA1c Is Associated with a Large
Reduction in Complications
Stratton IM, et al. BMJ. 2000;321(7258):405-412.
12% Stroke
Microvascular
complications (eg, kidney
disease and blindness)
37%
Amputation or fatal
peripheral blood vessel
disease
43%
Deaths related to diabetes21%
Heart attack14%
HbA1c
1%
Recommended Glycaemic Treatment Targets*
A Global Standard?
American Diabetes
Association1 IDF2 AACE3
HbA1c (%) <7.0 <7.0 ≤6.5
FPG mmol/L
(mg/dL)
<3.9-7.2
(70-130)
<6.5
(<115)
<6.1
(<110)
PPG mmol/L
(mg/dL)
<10
(<180)†
<9.0
(<160)†
7.8
(<140)‡
*Treatment targets for non-pregnant adults; †Measured at 1-2 hours following a meal;‡Measured at 2 hours following a meal.
AACE = American Association of Clinical Endocrinologists; IDF = International Diabetes Federation.
1. American Diabetes Association. Diabetes Care. 2013;36(Suppl 1):S11-S66. 2.IDF. Available at:
http://www.idf.org/sites/default/files/IDF%20T2DM%20Guideline.pdf. Accessed 29 August 2013. 3. Handelsman Y, et al. Endocr
Pract. 2011;17(Suppl 2):1-53.
A Combination of FBG and PPG contribute
to HbA1c
• The relative contribution of PPG and FBG varies with HbA1c
Monnier L, et al. Diabetes Care. 2003;26(3):881-885.
HbA1c Range (%)
Contribution(%)
PPG
FBG
<7.3 7.3-8.4 8.5-9.2 9.3-10.2 >10.2
0
20
40
60
80
100
Postprandial, Not Fasting, Glucose Is
Associated with MI and Mortality Risk
Blood Glucose (mmol/L)
300
200
100
0
IncidenceRateper1000Patients
n=994
FPG PPG
4.4-6.1 ≤7.8 >7.8 4.4-8.0 ≤10.0 >10.0
MI = myocardial infarction.
Hanefeld M, et al. Diabetologia. 1996;39(12):1577-1583.
Diabetes Intervention Study: 11-year Follow-up
MI
Mortality
300
200
100
0
P<.05
P<.05
• What are the treatment options from guideline to
practice ?
9
IDF Treatment Algorithm for People
with Type 2 Diabetes
DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; TZD = thiazolidinedione.
DF. Available at: http://www.idf.org/sites/default/files/IDF%20T2DM%20Guideline.pdf. Accessed 29 August 2013
Then, at each step, if not to target (generally HbA1c <7.0%)
Consider first line
Basal +
mealtime
insulin
Consider second line
Consider third line
Consider fourth line
Basal insulin, or
premixed insulin
(later basal + mealtime)
or
Basal insulin
or
Premixed insulin
or
AGI or DPP-4 inhibitor or
TZD
GLP-1 receptor
agonist
or
Metformin
(if not first time)
AGI or DPP-4 inhibitor or
TZDSulfonylurea
Metformin
Sulfonylurea
or
AGI
Usual approach
Alternative approach
Lifestyles measures
American Diabetes Association/EASD Joint Position Statement
General Therapy Recommendations in Type 2 Diabetes
DPP-4i = DPP-4 inhibitor; GI = gastrointestinal; RA = receptor agonist; HF = heart failure; SU = sulphonylurea.
Inzucchi SE, et al. Diabetes Care. 2012;35(6):1364-1379.
Inzucchi SE, et al. Diabetes Care. 2012;35(6):1364-1379.
American Diabetes Association/EASD Joint Position Statement
Key Points1
 Glycaemic targets and blood-glucose-lowering therapies must be
individualised
 Diet, exercise, and education: foundation of any type 2 diabetes therapy
program
 Unless contraindicated, metformin is the optimal 1st-line drug
 After metformin, data are limited. Combination therapy with an additional 1
to 2 oral or injectable agents is reasonable, but aim to minimise side effects
 Insulin therapy alone or in combination with other agents may be necessary
for many patients
 Treatment decisions should be made from a patient-centred approach
 Cardiovascular risk reduction must be an important focus of therapy
Mean reduction in A1c
mod. from Nathan D et al. Diabetologia 2008; 51:8-11
drug Route of
administration
Introduction/
FDA-approval
Mean reduction in A1c
(monotherapy)
Insulin sc 1921 ≥ 2,5
Sulfonylureas oral 1946 1,5
Metformin oral 1995 1,5
Alpha-Glucosidase
inhibitors
oral 1995 0,5 – 0,8
Glitazones oral 1997- 1999 0,8 – 1,0
GLP-1-agonist sc 2005 0,6
DPP-IV Inhibitors oral 2006 0,5 – 0,9
However over time,
most type 2 diabetics will also need
both basal and mealtime insulin
to control glucose
6-
19
When Oral Medications Are Not Enough
• Watch for the following signs
– Increasing BG levels
– Elevated A1C
– Unexplained weight loss
– Traces of ketonuria
– Poor energy level
– Sleep disturbances
– Polydipsia
• Next steps
– Make a decision to start insulin
– Offer patient encouragement, not blame
Remind the patient of disease progression…
Typical Diagnosis of Diabetes
Severity of Glucose Intolerance
Years
to
Decade
s
Normal Blood
Glucose
NATURAL HISTORY OF TYPE 2 DIABETES
Risk of Macrovascular Complications
Insulin
Resistance
IGT
Insulin Secretion
Postprandial Glucose
Risk of Microvascular Complications
Frank
Diabetes
NGT
Worsens
with Time
• The risk for hypoglycemia in type 2 diabetes
is low, and newer insulin analogs have
demonstrated even lower rates of
hypoglycemia than older insulin products.
• Although weight gain can be expected with
insulin (similar to that seen with
secretagogues), the benefits of glycemic
control clearly exceed the small increases in
body weight. 17
• Of note, insulin has been shown to reduce
mortality postmyocardial infarction,and more
than 10 years of follow-up in the United Kingdom
Prospective Diabetes Study (UKPDS) have
clearly shown no increase in cardiovascular risk.
• Finally, although multiple daily injections may be
required for patients with advanced, uncontrolled
diabetes, simpler insulin regimens are often
highly effective if initiated earlier in the course of
diabetes
18
Premix vs. Basal-Bolus: It’s all about life style
Factor Premix Regimen Basal Bolus Regimen
Injection frequency Prefers fewer injections No problem with more injections
SMBG Unwilling to self monitor Willing to self monitor
Daily routine Fixed Variable
Ability to follow regimen Limited cognitive function
Motivated with good cognitive
function
Support-education and
emotional
Essential Extremely essential
Adapted from: Liebl, et al. Int J Clin Pract, 2009;63(Suppl 164):1-5.
Patient centered approach
The INSTIGATE study reported on treatment patterns for
insulin initiation in major European countries.
• The most common first insulin in Germany was rapid acting insulin only
(34%)
• UK and Greece mixtures were the most common first insulin (48%).
• In France and Spain, basal insulin was the most common initial insulin.
In the recently published CREED Study involving countries
from Middle East, North Africa and Western Pacific,
• 50% of patients were treated with twice daily insulin regimens
20
Leibl A et al. - Current Medical Research & Opinion Vol. 27, No. 5, 2011, 887–895
• Premixed Vs basal insulin in type 2 DM :
21
22
Study Design
• Primary objective: HbA1c
• Secondary objectives: 2-hr postprandial blood glucose (BG), other BG values,
insulin dose, and hypoglycemia rate
• 32 week, multicenter, randomized, open-label crossover study
• Patients: 105 insulin-naïve adults with type 2 diabetes
• Treatments: Humalog Mix25 BID plus Met (1500-2550 mg/d) or Lantus at
bedtime plus Met (1500-2550 mg/d) for 16 weeks
Humalog® Mix25™ (BID) Plus Metformin (Met) vs
Lantus® Once Daily Plus Met in Pts New to Insulin
Malone JK et al. Clin Ther 2004;26:2034-2044.
Lantus + Met
0 16
Weeks
32-6 to -10
Lead-in
Humalog Mix25
(BID) + Met
Humalog Mix25
(BID) + Met
Lantus + Met
NPH + Met
Malone JK et al. Clin Ther 2004;26:2034-2044.
Humalog® Mix25™ (BID) Plus Metformin (Met) vs
Lantus® Once Daily Plus Met in Pts New to Insulin
-2
0
2
4
6
8
10
Lantus +
Met
Mix25 + Met
8.7 7.8
-
0.93
8.
7
7.4
-
1.32
p<0.001 p<0.001
*
†
Baseline (N=71 type
2 DM pts)
Endpoint (N=71)
Change from baseline
(N=67)
MeanHbA1c(%)
Daily insulin dose
(Mean ±SD)(U/kg) 0.57 ±0.37
**
0.62 ±0.37 **
p<0.001Data derived from Malone JK et al. Clin Ther 2004;26:2034-2044.
Mix25 + Met associated with lower mean HbA1c
and greater change in mean HbA1c compared with Lantus + Met
Higher percentage of patients treated with
Mix25 + Met attain treatment targets except
fasting blood glucose
Lantus + Met
0
10
20
30
40
50
60
70
80
90
HbA1c values
≤ 7.0%
FBG
≤ 7 mmol/L
AM pp BG*
≤ 10mmol/L
PM pp BG*
≤ 10mmol/L
Percentageofpatients
Mix25 + Met
p<0.001
p=0.036
p=0.019
p<0.001
* postprandial blood glucose
Data derived from Malone JK et al. Clin Ther 2004;26:2034-2044.
Humalog® Mix25™ (BID) Plus Metformin (Met) vs
Lantus® Once Daily Plus Met in Pts New to Insulin:
Overall and Nocturnal Hypoglycemia
Episodes/patient/30days
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
Lantus +
Met
Lantus +
Met
Mix25 +
Met
Mix25 +
Met
0
0.05
0.10
0.15
0.20
0.25
p=0.041
p=NS
Overall hypoglycemia Nocturnal hypoglycemia
N=101 N=100 N=101 N=100
Data derived from Malone JK et al. Clin Ther 2004;26:2034-2044.
Humalog® Mix25™ (BID) Plus Metformin (Met) vs
Lantus® Once Daily Plus Met in Pts New to Insulin: Summary
Mix25 BID + Met compared with Lantus + Met (patient
population with oral antidiabetic agent failure):
 Associated with significantly greater HbA1c reduction at 32
weeks
 Enabled a larger proportion of the treatment population to
attain HbA1c ≤7.0%, despite significantly higher fasting blood
glucose levels
 Improved glycemic control after breakfast and dinner
 Resulted in higher overall hypoglycemia rate but similar rate
of nocturnal hypoglycemia
Malone JK et al. Clin Ther 2004;26:2034-2044.
A Study Comparing Insulin Lispro Mix 25 With
Glargine Plus Lispro Therapy in Patients With Type 2
Diabetes Who Have Inadequate Glycaemic Control
on Oral Antihyperglycaemic Medication:
Results of the PARADIGM Study
K. Bowering1, V. A. Reed2, J. Felicio3,
J. Landry4, L. Ji5 and J. Oliveira6
1University of Alberta, Division of Endocrinology and Metabolism in the Department of Medicine,
Edmonton, AB, Canada; 2Eli Lilly and Company, Asia-Pacific Medical Communications, Sydney,
NSW, Australia; 3Universidade Federal do Pará, Endocrinology Division, Belém, Brazil; 4Eli Lilly
Canada Inc., Toronto, ON, Canada; 5Peking University People’s Hospital, Department of
Endocrinology and Metabolism, Beijing, China; 6Eli Lilly and Company, Indianapolis, IN, USA
Primary Objective
 A 48-week, randomized, open-label, active-controlled
study conducted to
̶ Assess initiation and intensification with LM25 therapy
̶ Determine if initiation and intensification with glargine plus insulin
lispro, in terms of glycaemic control are comparable (non-inferior),
as measured by change in HbA1c from baseline
 In patients with T2D inadequately controlled with oral antihyperglycaemic
medications
Bowering et al. Diabet Med 2012;29(9):e263-72.
Study Design
Randomization
Bowering et al. Diabet Med 2012;29(9):e263-72.
• LM25: 25% insulin lispro, 75% insulin lispro protamine suspension once daily, progressing up to thrice
daily, G + L: insulin glargine once daily alone, progressing up to 3 additional insulin lispro injections
• QD: once daily, TID: thrice daily, G: insulin glargine, L: insulin lispro injection
Measures
 Primary
̶ Change in HbA1c from baseline to endpoint
 Secondary
̶ Percentage of patients achieving HbA1c targets of ≤48 mmol/mol (≤6.5%) and
<53 mmol/mol (<7.0%) at endpoint
̶ Postprandial blood glucose
̶ Daily total insulin dose
̶ 7-point self-monitored blood glucose profiles
̶ Lipid and cholesterol profiles
 Exploratory
̶ Patient evaluation of Qol (EQ-5D)
̶ Patient evaluation of disease-specific Qol (DHP-18)
 Safety
̶ Events related to hypoglycaemia were assessed as to incidence, rate, and
severity
Bowering et al. Diabet Med 2012;29(9):e263-72.
LS Mean Change in HbA1C From Baseline to
Endpoint
Bowering et al. Diabet Med 2012;29(9):e263-72.
• HbA1c: hemoglobin A1c, G: insulin glargine, L: insulin lispro injection
8.98
7.1
9.03
7.3
0
1
2
3
4
5
6
7
8
9
10
Baseline A1c Endpoint A1c
LSMeanChangeinHbAic(%)
LM25
G + L
Insulin Dose and Number of Injections at
Week 48
Treatment Groups
LM25
n=177
G + L
n=184
Mean insulin dose, U/Kg (SD) 0.71 (0.45) 0.71 (0.47)
Mean number of daily injections (SD) 2.14 (0.75) 2.25 (1.20)
Injection regimen, patients, n (%)
One 40 (22.6) 79 (42.9)
Two 74 (41.8) 20 (10.9)
Three 63 (35.6) 49 (26.6)
Four 36 (19.6)
Bowering et al. Diabet Med 2012;29(9):e263-72.
• LM25: insulin lispro mix 25, 25% lispro, 75% insulin lispro protamine suspension, G: insulin glargine,
L: insulin lispro injection, SD: standard deviation
Humalog Mix 25 flexible dosing regimen
35
(% of patients)
Bowering et al. Diabet Med 2012;29(9):e263-72.
Similar hypoglycemia rates were observed
between treatment groups.
86.7
75.4
2.8
84.8
71.6
3.4
0
20
40
60
80
100
Overall
Hypoglycaemia
Nocturnal
Hypoglycaemia
Severe
Hypoglycaemia
IncidenceofHypoglycaemia(%)
G + L, n=184
LM25, n=177
Oliveira et al. Diabetes. 2010;59(Suppl 1):A171-2 [628-P].
• LM25: insulin lispro mix 25, 25% lispro, 75% insulin lispro protamine suspension, G: insulin
glargine, L: insulin lispro injection
Key Findings
 This is the first randomised controlled study to investigate
treatment with LM25 initiated as a once-daily therapy and
with the option to be intensified up to three times a day, in
insulin-naїve patients with Type 2 diabetes
 The results show that initiating and intensifying insulin therapy
with LM25 was non-inferior to initiating and intensifying insulin
treatment with glargine + insulin lispro, as measured by
change in HbA1c from baseline to study end
 Hypoglycaemia incidence was also not statistically different
between the two groups
Bowering et al. Diabet Med 2012;29(9):e263-72.
Case
• 65 year old male lawyer has had DM for 14 year, and his
recent PPG after lunch is 354 mg/dl despite increasing the
dose of basal insulin
• Patient is usually taking heavy carbohydrate meals
• Previous heart attack and is taking several cardiovascular
and hypertensive medications
• BMI of 32
• Admits to feeling a little tired recently
• ↑ frequency of micturition for 2-3 times/week
Clinical Profile
Age: 65
BMI: 32
Blood Glucose
Last A1C: 10.2%
PPG after lunch: 354
mg/dL
Lipid Profile
Total: 153 mg/dL
LDL: 70 mg/dL
HDL: 41 mg/dL
Triglycerides: 225 mg/dL
Kidney Profile
Creatinine: 0.8 mg/dL
Microalbuminuria:
Negative
Liver Function
ALT: normal
AST: normal
Blood Pressure
Normal: 130/90 mmHg
Cardiovascular
condition Previous
myocardial infarction
Eye Exam
Normal
Foot Exam
Normal pulses and
sensation
Two questions that may be relevant
1. Add one injection of rapid acting insulin to
basal insulin or switch to premix?
2. How should I think about increasing dose
frequency?
Ueda2015 lilly.the art of insulin dr.mesbah sayed
• Does insulin Initiation Guarantee Good Glycaemic Control ?
Insulin initiation does not necessarily result in HbA1c reduction.
 UK: 73% of patients maintained an HbA1c ≥7.5%, 6-months post insulin
initiation1
Insulin treatment does not necessarily result in achieving goal HbA1c.
 The INITIATE study, a 28-week parallel designed, randomized study,
showed that 40% of patients on basal therapy and 66% of patients on
premix achieved the target HbA1c of <7%2
 The Treat to Target trial (4T) reported that 42% of patients adding basal
insulin to oral therapy did not reach an HbA1c ≤7%3
 The International Diabetes Management Practice Study (IDMPS), listed
attainment of HbA1c goal (<7%) in patients with type 2 diabetes to be
37% (Asia), 36% (Eastern Europe), and 36% (Latin America) among
patients treated with insulin4
Insulin Initiation Does Not Guarantee Good Glycaemic
Control
INITIATE = Initiate Insulin by Aggressive Titration and Education.
1. Calvert MJ, et al. Br J Gen Pract. 2007;57(539):455-460. 2. Raskin P, et al. Diabetes Care. 2005;28(2):260-265. 3. Riddle MC,
et al. Diabetes Care. 2003;26(11):3080-3086. 4. Chan JC, et al. Diabetes Care. 2009;32(2):227-233.
Basal insulin only
(usually with oral agents)
Non-insulin regimens
Basal insulin + 1
(mealtime) rapid-
acting insulin
injection
Premixed insulin
twice daily
Basal insulin + ≥2
(mealtime) rapid-
acting insulin
injections
low
mod.
high
1
2
3+
Number of
injections
Regimen
complexity
More flexible Less flexible Flexibility
Therapy following Basal Only Insulin
Inzucchi SE, et al. Diabetes Care. 2012;35(6):1364-1379.
If Basal insulin
fails, what is the
next best
approach?
IDF Treatment Algorithm for People
with Type 2 Diabetes
DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; TZD = thiazolidinedione.
DF. Available at: http://www.idf.org/sites/default/files/IDF%20T2DM%20Guideline.pdf. Accessed 29 August 2013
Then, at each step, if not to target (generally HbA1c <7.0%)
Consider first line
Basal +
mealtime
insulin
Consider second line
Consider third line
Consider fourth line
Basal insulin, or
premixed insulin
(later basal + mealtime)
or
Basal insulin
or
Premixed insulin
or
AGI or DPP-4 inhibitor or
TZD
GLP-1 receptor
agonist
or
Metformin
(if not first time)
AGI or DPP-4 inhibitor or
TZDSulfonylurea
Metformin
Sulfonylurea
or
AGI
Usual approach
Alternative approach
Lifestyles measures
If Basal insulin
fails, what is the
next best
approach?
Second-line insulin choices in type 2
diabetes: patient factors
Basal-bolus Premix Basal plus
Patient preference for fewest injections + +
Variable meal pattern + +
Variable daily routine +
Limited capability (eg, cognitive
function, dexterity) +
Better postprandial control required + +
Unwilling to self-monitor several times
daily +
Limited support (family, general
practitioner) + +
Reference:
Modified from Barnett A et al. Int J Clin Pract. 2008; 62:1647-1653
• Humalog Mix50
– mimics physiological insulin secretion to provide tighter
PPG control
In Non-diabetic Individuals, Basal Secretion Represents
Approximately 50% Total Daily Insulin
Data from Polonsky KS et al. J Clin Invest 1988; 81:442-48
Normal
Obese
Extrapolated Basal Secretion
50.1±3.1% Normal subjects
45.2±2.2% Obese subjects
0
100
200
300
400
500
600
PercentBasalInsulinSecretion
0600 1000 1400 1800 2200 0200 0600
Clock Hours
* After a test meal.
Data derived from: Schwartz S, et al. Clin Ther. 2006;28:1649-1657.
Schwartz S, et al. Diabetologia 2003;46(suppl 2):A267.
Humalog® Mix50™ Tight Mealtime Control
Increasing the proportion of rapid-acting insulin improves PPG*
• PPG decreased as proportion of rapid-acting insulin increased
• Basal-only insulin was associated with highest PPG of the 4 regimens
2-hrPPG(mmol/L)
Each regimen resulted in
PPG significantly different from all other
regimens (pairwise comparison). P<0.05.
Glargine Human Insulin
30/70
Humalog®
Mix25™
Humalog®
Mix50™
Patients
without diabetes
Humalog Mix50 injected three times daily comparison with
human insulin 30/70
Metabolic control in patients with type 2 diabetes using Humalog Mix50
injected three times daily: crossover comparison with human insulin
30/70
• Objectives
– This study was designed to compare metabolic control with three
daily injections of Humalog Mix50 or premixed human insulin 30/70
(30% regular/70% NPH) twice daily in accordance with normal
prescription practice
• Patients and methods
– The study cohort of 40 patients with type 2 diabetes used a two-
way, crossover design. Patients were randomized to either Mix50 at
each main meal or human insulin 30/70 at breakfast and dinner for
3 months, followed by the alternate treatment for 3 months
– Blood glucose was measured by the patients at baseline and at the
end of each treatment sequence
– No significant carryover effects were observed, so treatment
sequences were combined and data analyzed by unpaired t-tests
Schernthaner G et al. Horm Metab Res. 2004; 36: 188-193.
LM50 TID vs. Humulin 30/70 BID:
endpoint A1C
LM50=50% insulin lispro/50% insulin lispro protamine suspension; Humulin 30/70=30% regular human insulin/70% human
insulin isophane suspension.
MeanA1C(%)
6.0
7.0
8.0
9.0
LM50 TIDHumulin 30/70Baseline
p<0.001
8.4%
8.1%
7.6%
p=0.021p=0.034
6.5
7.5
8.5
Schernthaner G et al. Horm Metab Res. 2004; 36: 188-193.
2-hour postprandial reductions in postprandial glucose were significantly greater
with LM50 TID than those observed in Humulin 30/70 treatment (p0.001)
*p<0.001 compared to baseline and Humulin 30/70. N=35 patients with type 2 diabetes mellitus. 24-week crossover.
LM50=50% insulin lispro/50% insulin lispro protamine suspension; Humulin 30/70=30% regular human insulin/70% human
insulin isophane suspension.
Postprandialblood
glucose(mmol/L)
6
8
10
12
After dinnerAfter lunchAfter breakfast
LM50 TID
Humulin 30/70
Baseline
*
*
Schernthaner G et al. Horm Metab Res. 2004; 36: 188-193.
Metabolic control in patients with type 2 diabetes using
Humalog Mix50 injected three times daily: crossover
comparison with human insulin 30/70
Study summary and conclusions
– The decrease from baseline in A1C was significantly greater with
Mix50 than with 30/70 insulin
– There were no significant differences between treatments
regarding incidence of hypoglycemia or adverse events
– In patients with type 2 diabetes, a regimen of Humalog Mix50
administered three times daily before meals maintains glucose
control more effectively than premixed human insulin 30/70
administered before breakfast and dinner
Schernthaner G et al. Horm Metab Res. 2004; 36: 188-193.
Two questions that may be relevant
1. Add one injection of rapid acting insulin to basal
insulin or switch to premix?
2. How should I think about increasing
dose frequency?
Basal insulin only
(usually with oral agents)
Non-insulin regimens
Basal insulin + 1
(mealtime) rapid-
acting insulin
injection
Premixed insulin
twice daily
Basal insulin + ≥2
(mealtime) rapid-
acting insulin
injections
low
mod.
high
1
2
3+
Number of
injections
Regimen
complexity
More flexible Less flexible Flexibility
Therapy following Basal Only Insulin
Inzucchi SE, et al. Diabetes Care. 2012;35(6):1364-1379.
How can you
add prandial
insulin?
AUTONOMY: The First Randomized Trial Comparing
Two Patient-driven Approaches to Initiate and Titrate
Prandial Insulin Lispro in
Type 2 Diabetes
Steve V. Edelman,1 Rong Liu,2 Jennal Johnson,2 Leonard C. Glass2
1University of California, San Diego Department of Medicine;
2Eli Lilly and Company, Indianapolis, IN, USA
Edelman et al. Diabetes Care 2014;(Ahead of print).
AUTONOMY: Study Objective
• To compare efficacy and safety of 2 patient-based
self-titration algorithms for initiation and titration of prandial insulin
lispro in patients with type 2 diabetes inadequately controlled on
basal insulin plus OADs in endocrine and generalist settings
• Monitoring was done every day or every 3 days
– Approximately 44% of trial sites were in primary care settings
• 1st comparison of 2 self-titration insulin algorithms for escalation of
prandial insulin lispro therapy in a large, multicountry, randomized,
controlled trial
Edelman et al. Diabetes Care 2014;(Ahead of print).
AUTONOMY: Study Design
Discontinue
HbA1c ≤7.0%
(≤53.0 mmol/mol)
Randomize
Enrollment
Add insulin lispro 1-2-3
with adjustments
(Q1D)
Add insulin lispro 1-2-3
with adjustments
(Q3D)
NO
6 Weeks 24 Weeks
Visit: 1 (screening) 2a 3a 4a,b 5a,b 6a 7a 8b 9b 10 11b 12 13b 14b 15 16b 17 18b 19
Week: -1 0 1 2 4 6 7 8 9 10 12 14 16 18 19 23 27 29 31
a6-week GLA optimization lead-in only required for subjects who had to be converted to GLA from insulin NPH, ILPS,
or detemir; required conversion from GLA twice daily to once daily; or those on once-daily GLA at study entry with
HbA1c >7.0% (>53.0 mmol/mol) and fasting blood glucose >120 mg/dL (>6.7 mmol/L). Subjects who did not require GLA
optimization were randomized at Visit 2, forewent Visits 3 to 7 and instead proceeded to the randomized treatment period
beginning with Visit 8 activities, 1 week after Visit 2; bTelephone visits
Optional: Insulin
Glargine (GLA)
Optimization
Lead-ina
YES
Edelman et al. Diabetes Care 2014;(Ahead of print).
AUTONOMY: Primary and Secondary
Outcome Measures
• Primary efficacy outcome:
– Compare change in HbA1c from baseline to endpoint (Week 24 after
randomization) for Q1D and Q3D algorithms
• Secondary outcomes:
– Incidence and annualized rate of self-reported total, severe, and nocturnal
hypoglycemia
– Proportion of subjects achieving target values HbA1c ≤7.0%
– Change in FBG, 7-point SMBG profile, and weight from baseline
– Change in dose of basal (GLA) and prandial (lispro) insulin at end of study
– Change in 1,5-anhydroglucitol (a marker of hyperglycemia)
• Assessments in subjects ≥65 years of age:
– Change in HbA1c, hypoglycemia (incidence and rate), FBG, and proportion of
subjects achieving target
• Safety was monitored throughout the study (hypoglycemia was
considered an AE with severe hypoglycemia recorded as an SAE)
Edelman et al. Diabetes Care 2014;(Ahead of print).
AUTONOMY: Proportion Achieving HbA1c
≤7.0%
*p<0.05 for Q3D vs. Q1D; p-values were computed based upon a logistic regression model with effects for treatment
algorithms and strata
Study A (N=528) Study B (N=578)
p=0.015p=0.162p=0.701p=0.128
*
Edelman SV. Diabetes Care 37:2132-40, 2014
AUTONOMY: Change From Baseline
Weight
*p<0.05 for Q3D vs. Q1D; data were reported as LSM ± SE of the mean based upon from a MMRM that included baseline
weight, strata, treatment algorithm, visit, and treatment algorithm by visit
Weight(kg)ChangefromBaseline
(LSM±SE)
p=0.014 p=0.108
*
Edelman SV. Diabetes Care 37:2132-40, 2014
AUTONOMY: Discussion (Slide 1 of 2)
• Both algorithms (Q1D, Q3D) demonstrated statistically significant
and clinically equivalent reductions in HbA1c, significant increases
in 1,5-AG, and improved 7-point SMBG profiles in Studies A and B
• ~50% of subjects who had previously failed to reach goal HbA1c of
≤7.0% (53.0 mmol/mol) with basal insulin optimization plus OADs
achieved the ADA goals for glycemic control with less glucose
variability
• Sequential addition of prandial insulin lispro injections resulted
in ~61% of subjects only requiring ≤2 doses rather than a full
basal-bolus regimen (ie, simplifies treatment, could enhance
therapy compliance)
• Subjects gained 2-3 kg of weight, regardless of treatment algorithm,
with the initiation of prandial insulin
Edelman et al. Diabetes Care 2014;(Ahead of print).
• Results show basal-bolus therapy can be initiated in the elderly
without increased risk of hypoglycemia
• Regardless of titration algorithm, improved metabolic control was
accomplished with low incidences and rates of nocturnal and severe
hypoglycemia in both the overall study population and the elderly
subgroup (≥65 years of age) with initiation and escalation of lispro
AUTONOMY: Discussion (Slide 2 of 2)
Edelman et al. Diabetes Care 2014;(Ahead of print).
Conclusions
Putting it into Practice
• Recognise that the challenges of diabetes management for
patients require a patient-centred approach
• Patient education in order to optimise the types of behavioural
modifications that support effective self-care habits
• Thank you

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Ueda2015 lilly.the art of insulin dr.mesbah sayed

  • 1. The Art and Science of Insulin Role of Modern Basal/Prandial Insulins inType 2DM Mesbah Sayed Kamel MD
  • 2. Disclosures • I have provided services ( speaker, advisor, consultant and investigator in clinical trials ) for the following companies: Novo Nordisk, MSD,Sanofi Aventis, Novartis ,Lilly,Astra Zenica&Merck Sorono. • For these activities I received appropriate honoraria and/or grant support. 2
  • 3. Clinical Challenge Person with Type 2 Diabetes on Oral Therapies but HbA1c Is 9.4%* Case Presentation:  Age: 52 years  Duration of type 2 diabetes: 7 years  Review of patient logbook shows FPG of 9.9-16.3 mmol/L (178.2-293.4 mg/dL) over the past 2 months  Weight: 209 lbs (95 kg)  BMI: 31.8 kg/m2  Blood pressure: 135/85 mmHg  Current treatment: glipizide 10 mg QD, metformin 1000 mg BID  No reported hypoglycaemia Lab Results:  FPG: 10.4 mmol/L (187.2 mg/dL)  2-hour PPG: 14.7 mmol/L (264.6 mg/dL)  Total cholesterol: 4.7 mmol/L (181.5 mg/dL)  Triglycerides: 1.9 mmol/L (168.1 mg/dL)  AST: 15 IU/L  ALT: 19 IU/L  HbA1c: 9.4%  Urine microalbumin: 18 mg/24 hr What therapeutic decisions would you make to help this patient reach his or her HbA1c goal? *Hypothetical patient case. ALT = alanine transaminase; AST = aspartate transaminase; BID = two times per day; BMI = body mass index; FPG = fasting plasma glucose; PPG = postprandial plasma glucose; QD = once per day. Patient Perspective:  Wants to improve glycaemic control and is willing to add an injectable therapy …but wants to minimise the number of injections  Has a fairly predictable daily routine, including meal composition
  • 4. ARS = audience response system; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; TZD = thiazolidinedione. ARS Question What would be the next step in therapy for this patient? a) No change to therapy – monitor HbA1c again in 3 months b) Add an additional oral agent (eg, TZD, DPP-4 inhibitor) c) Add a basal insulin at bedtime d) Stop glipizide, begin a premixed insulin analogue therapy e) Stop orals and start basal/bolus insulin therapy f) Add a GLP-1 receptor agonist
  • 5. UKPDS A 1% Decrease in HbA1c Is Associated with a Large Reduction in Complications Stratton IM, et al. BMJ. 2000;321(7258):405-412. 12% Stroke Microvascular complications (eg, kidney disease and blindness) 37% Amputation or fatal peripheral blood vessel disease 43% Deaths related to diabetes21% Heart attack14% HbA1c 1%
  • 6. Recommended Glycaemic Treatment Targets* A Global Standard? American Diabetes Association1 IDF2 AACE3 HbA1c (%) <7.0 <7.0 ≤6.5 FPG mmol/L (mg/dL) <3.9-7.2 (70-130) <6.5 (<115) <6.1 (<110) PPG mmol/L (mg/dL) <10 (<180)† <9.0 (<160)† 7.8 (<140)‡ *Treatment targets for non-pregnant adults; †Measured at 1-2 hours following a meal;‡Measured at 2 hours following a meal. AACE = American Association of Clinical Endocrinologists; IDF = International Diabetes Federation. 1. American Diabetes Association. Diabetes Care. 2013;36(Suppl 1):S11-S66. 2.IDF. Available at: http://www.idf.org/sites/default/files/IDF%20T2DM%20Guideline.pdf. Accessed 29 August 2013. 3. Handelsman Y, et al. Endocr Pract. 2011;17(Suppl 2):1-53.
  • 7. A Combination of FBG and PPG contribute to HbA1c • The relative contribution of PPG and FBG varies with HbA1c Monnier L, et al. Diabetes Care. 2003;26(3):881-885. HbA1c Range (%) Contribution(%) PPG FBG <7.3 7.3-8.4 8.5-9.2 9.3-10.2 >10.2 0 20 40 60 80 100
  • 8. Postprandial, Not Fasting, Glucose Is Associated with MI and Mortality Risk Blood Glucose (mmol/L) 300 200 100 0 IncidenceRateper1000Patients n=994 FPG PPG 4.4-6.1 ≤7.8 >7.8 4.4-8.0 ≤10.0 >10.0 MI = myocardial infarction. Hanefeld M, et al. Diabetologia. 1996;39(12):1577-1583. Diabetes Intervention Study: 11-year Follow-up MI Mortality 300 200 100 0 P<.05 P<.05
  • 9. • What are the treatment options from guideline to practice ? 9
  • 10. IDF Treatment Algorithm for People with Type 2 Diabetes DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; TZD = thiazolidinedione. DF. Available at: http://www.idf.org/sites/default/files/IDF%20T2DM%20Guideline.pdf. Accessed 29 August 2013 Then, at each step, if not to target (generally HbA1c <7.0%) Consider first line Basal + mealtime insulin Consider second line Consider third line Consider fourth line Basal insulin, or premixed insulin (later basal + mealtime) or Basal insulin or Premixed insulin or AGI or DPP-4 inhibitor or TZD GLP-1 receptor agonist or Metformin (if not first time) AGI or DPP-4 inhibitor or TZDSulfonylurea Metformin Sulfonylurea or AGI Usual approach Alternative approach Lifestyles measures
  • 11. American Diabetes Association/EASD Joint Position Statement General Therapy Recommendations in Type 2 Diabetes DPP-4i = DPP-4 inhibitor; GI = gastrointestinal; RA = receptor agonist; HF = heart failure; SU = sulphonylurea. Inzucchi SE, et al. Diabetes Care. 2012;35(6):1364-1379.
  • 12. Inzucchi SE, et al. Diabetes Care. 2012;35(6):1364-1379. American Diabetes Association/EASD Joint Position Statement Key Points1  Glycaemic targets and blood-glucose-lowering therapies must be individualised  Diet, exercise, and education: foundation of any type 2 diabetes therapy program  Unless contraindicated, metformin is the optimal 1st-line drug  After metformin, data are limited. Combination therapy with an additional 1 to 2 oral or injectable agents is reasonable, but aim to minimise side effects  Insulin therapy alone or in combination with other agents may be necessary for many patients  Treatment decisions should be made from a patient-centred approach  Cardiovascular risk reduction must be an important focus of therapy
  • 13. Mean reduction in A1c mod. from Nathan D et al. Diabetologia 2008; 51:8-11 drug Route of administration Introduction/ FDA-approval Mean reduction in A1c (monotherapy) Insulin sc 1921 ≥ 2,5 Sulfonylureas oral 1946 1,5 Metformin oral 1995 1,5 Alpha-Glucosidase inhibitors oral 1995 0,5 – 0,8 Glitazones oral 1997- 1999 0,8 – 1,0 GLP-1-agonist sc 2005 0,6 DPP-IV Inhibitors oral 2006 0,5 – 0,9
  • 14. However over time, most type 2 diabetics will also need both basal and mealtime insulin to control glucose 6- 19
  • 15. When Oral Medications Are Not Enough • Watch for the following signs – Increasing BG levels – Elevated A1C – Unexplained weight loss – Traces of ketonuria – Poor energy level – Sleep disturbances – Polydipsia • Next steps – Make a decision to start insulin – Offer patient encouragement, not blame Remind the patient of disease progression…
  • 16. Typical Diagnosis of Diabetes Severity of Glucose Intolerance Years to Decade s Normal Blood Glucose NATURAL HISTORY OF TYPE 2 DIABETES Risk of Macrovascular Complications Insulin Resistance IGT Insulin Secretion Postprandial Glucose Risk of Microvascular Complications Frank Diabetes NGT Worsens with Time
  • 17. • The risk for hypoglycemia in type 2 diabetes is low, and newer insulin analogs have demonstrated even lower rates of hypoglycemia than older insulin products. • Although weight gain can be expected with insulin (similar to that seen with secretagogues), the benefits of glycemic control clearly exceed the small increases in body weight. 17
  • 18. • Of note, insulin has been shown to reduce mortality postmyocardial infarction,and more than 10 years of follow-up in the United Kingdom Prospective Diabetes Study (UKPDS) have clearly shown no increase in cardiovascular risk. • Finally, although multiple daily injections may be required for patients with advanced, uncontrolled diabetes, simpler insulin regimens are often highly effective if initiated earlier in the course of diabetes 18
  • 19. Premix vs. Basal-Bolus: It’s all about life style Factor Premix Regimen Basal Bolus Regimen Injection frequency Prefers fewer injections No problem with more injections SMBG Unwilling to self monitor Willing to self monitor Daily routine Fixed Variable Ability to follow regimen Limited cognitive function Motivated with good cognitive function Support-education and emotional Essential Extremely essential Adapted from: Liebl, et al. Int J Clin Pract, 2009;63(Suppl 164):1-5.
  • 20. Patient centered approach The INSTIGATE study reported on treatment patterns for insulin initiation in major European countries. • The most common first insulin in Germany was rapid acting insulin only (34%) • UK and Greece mixtures were the most common first insulin (48%). • In France and Spain, basal insulin was the most common initial insulin. In the recently published CREED Study involving countries from Middle East, North Africa and Western Pacific, • 50% of patients were treated with twice daily insulin regimens 20 Leibl A et al. - Current Medical Research & Opinion Vol. 27, No. 5, 2011, 887–895
  • 21. • Premixed Vs basal insulin in type 2 DM : 21
  • 22. 22
  • 23. Study Design • Primary objective: HbA1c • Secondary objectives: 2-hr postprandial blood glucose (BG), other BG values, insulin dose, and hypoglycemia rate • 32 week, multicenter, randomized, open-label crossover study • Patients: 105 insulin-naïve adults with type 2 diabetes • Treatments: Humalog Mix25 BID plus Met (1500-2550 mg/d) or Lantus at bedtime plus Met (1500-2550 mg/d) for 16 weeks Humalog® Mix25™ (BID) Plus Metformin (Met) vs Lantus® Once Daily Plus Met in Pts New to Insulin Malone JK et al. Clin Ther 2004;26:2034-2044.
  • 24. Lantus + Met 0 16 Weeks 32-6 to -10 Lead-in Humalog Mix25 (BID) + Met Humalog Mix25 (BID) + Met Lantus + Met NPH + Met Malone JK et al. Clin Ther 2004;26:2034-2044. Humalog® Mix25™ (BID) Plus Metformin (Met) vs Lantus® Once Daily Plus Met in Pts New to Insulin
  • 25. -2 0 2 4 6 8 10 Lantus + Met Mix25 + Met 8.7 7.8 - 0.93 8. 7 7.4 - 1.32 p<0.001 p<0.001 * † Baseline (N=71 type 2 DM pts) Endpoint (N=71) Change from baseline (N=67) MeanHbA1c(%) Daily insulin dose (Mean ±SD)(U/kg) 0.57 ±0.37 ** 0.62 ±0.37 ** p<0.001Data derived from Malone JK et al. Clin Ther 2004;26:2034-2044. Mix25 + Met associated with lower mean HbA1c and greater change in mean HbA1c compared with Lantus + Met
  • 26. Higher percentage of patients treated with Mix25 + Met attain treatment targets except fasting blood glucose Lantus + Met 0 10 20 30 40 50 60 70 80 90 HbA1c values ≤ 7.0% FBG ≤ 7 mmol/L AM pp BG* ≤ 10mmol/L PM pp BG* ≤ 10mmol/L Percentageofpatients Mix25 + Met p<0.001 p=0.036 p=0.019 p<0.001 * postprandial blood glucose Data derived from Malone JK et al. Clin Ther 2004;26:2034-2044.
  • 27. Humalog® Mix25™ (BID) Plus Metformin (Met) vs Lantus® Once Daily Plus Met in Pts New to Insulin: Overall and Nocturnal Hypoglycemia Episodes/patient/30days 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 Lantus + Met Lantus + Met Mix25 + Met Mix25 + Met 0 0.05 0.10 0.15 0.20 0.25 p=0.041 p=NS Overall hypoglycemia Nocturnal hypoglycemia N=101 N=100 N=101 N=100 Data derived from Malone JK et al. Clin Ther 2004;26:2034-2044.
  • 28. Humalog® Mix25™ (BID) Plus Metformin (Met) vs Lantus® Once Daily Plus Met in Pts New to Insulin: Summary Mix25 BID + Met compared with Lantus + Met (patient population with oral antidiabetic agent failure):  Associated with significantly greater HbA1c reduction at 32 weeks  Enabled a larger proportion of the treatment population to attain HbA1c ≤7.0%, despite significantly higher fasting blood glucose levels  Improved glycemic control after breakfast and dinner  Resulted in higher overall hypoglycemia rate but similar rate of nocturnal hypoglycemia Malone JK et al. Clin Ther 2004;26:2034-2044.
  • 29. A Study Comparing Insulin Lispro Mix 25 With Glargine Plus Lispro Therapy in Patients With Type 2 Diabetes Who Have Inadequate Glycaemic Control on Oral Antihyperglycaemic Medication: Results of the PARADIGM Study K. Bowering1, V. A. Reed2, J. Felicio3, J. Landry4, L. Ji5 and J. Oliveira6 1University of Alberta, Division of Endocrinology and Metabolism in the Department of Medicine, Edmonton, AB, Canada; 2Eli Lilly and Company, Asia-Pacific Medical Communications, Sydney, NSW, Australia; 3Universidade Federal do Pará, Endocrinology Division, Belém, Brazil; 4Eli Lilly Canada Inc., Toronto, ON, Canada; 5Peking University People’s Hospital, Department of Endocrinology and Metabolism, Beijing, China; 6Eli Lilly and Company, Indianapolis, IN, USA
  • 30. Primary Objective  A 48-week, randomized, open-label, active-controlled study conducted to ̶ Assess initiation and intensification with LM25 therapy ̶ Determine if initiation and intensification with glargine plus insulin lispro, in terms of glycaemic control are comparable (non-inferior), as measured by change in HbA1c from baseline  In patients with T2D inadequately controlled with oral antihyperglycaemic medications Bowering et al. Diabet Med 2012;29(9):e263-72.
  • 31. Study Design Randomization Bowering et al. Diabet Med 2012;29(9):e263-72. • LM25: 25% insulin lispro, 75% insulin lispro protamine suspension once daily, progressing up to thrice daily, G + L: insulin glargine once daily alone, progressing up to 3 additional insulin lispro injections • QD: once daily, TID: thrice daily, G: insulin glargine, L: insulin lispro injection
  • 32. Measures  Primary ̶ Change in HbA1c from baseline to endpoint  Secondary ̶ Percentage of patients achieving HbA1c targets of ≤48 mmol/mol (≤6.5%) and <53 mmol/mol (<7.0%) at endpoint ̶ Postprandial blood glucose ̶ Daily total insulin dose ̶ 7-point self-monitored blood glucose profiles ̶ Lipid and cholesterol profiles  Exploratory ̶ Patient evaluation of Qol (EQ-5D) ̶ Patient evaluation of disease-specific Qol (DHP-18)  Safety ̶ Events related to hypoglycaemia were assessed as to incidence, rate, and severity Bowering et al. Diabet Med 2012;29(9):e263-72.
  • 33. LS Mean Change in HbA1C From Baseline to Endpoint Bowering et al. Diabet Med 2012;29(9):e263-72. • HbA1c: hemoglobin A1c, G: insulin glargine, L: insulin lispro injection 8.98 7.1 9.03 7.3 0 1 2 3 4 5 6 7 8 9 10 Baseline A1c Endpoint A1c LSMeanChangeinHbAic(%) LM25 G + L
  • 34. Insulin Dose and Number of Injections at Week 48 Treatment Groups LM25 n=177 G + L n=184 Mean insulin dose, U/Kg (SD) 0.71 (0.45) 0.71 (0.47) Mean number of daily injections (SD) 2.14 (0.75) 2.25 (1.20) Injection regimen, patients, n (%) One 40 (22.6) 79 (42.9) Two 74 (41.8) 20 (10.9) Three 63 (35.6) 49 (26.6) Four 36 (19.6) Bowering et al. Diabet Med 2012;29(9):e263-72. • LM25: insulin lispro mix 25, 25% lispro, 75% insulin lispro protamine suspension, G: insulin glargine, L: insulin lispro injection, SD: standard deviation
  • 35. Humalog Mix 25 flexible dosing regimen 35 (% of patients) Bowering et al. Diabet Med 2012;29(9):e263-72.
  • 36. Similar hypoglycemia rates were observed between treatment groups. 86.7 75.4 2.8 84.8 71.6 3.4 0 20 40 60 80 100 Overall Hypoglycaemia Nocturnal Hypoglycaemia Severe Hypoglycaemia IncidenceofHypoglycaemia(%) G + L, n=184 LM25, n=177 Oliveira et al. Diabetes. 2010;59(Suppl 1):A171-2 [628-P]. • LM25: insulin lispro mix 25, 25% lispro, 75% insulin lispro protamine suspension, G: insulin glargine, L: insulin lispro injection
  • 37. Key Findings  This is the first randomised controlled study to investigate treatment with LM25 initiated as a once-daily therapy and with the option to be intensified up to three times a day, in insulin-naїve patients with Type 2 diabetes  The results show that initiating and intensifying insulin therapy with LM25 was non-inferior to initiating and intensifying insulin treatment with glargine + insulin lispro, as measured by change in HbA1c from baseline to study end  Hypoglycaemia incidence was also not statistically different between the two groups Bowering et al. Diabet Med 2012;29(9):e263-72.
  • 38. Case • 65 year old male lawyer has had DM for 14 year, and his recent PPG after lunch is 354 mg/dl despite increasing the dose of basal insulin • Patient is usually taking heavy carbohydrate meals • Previous heart attack and is taking several cardiovascular and hypertensive medications • BMI of 32 • Admits to feeling a little tired recently • ↑ frequency of micturition for 2-3 times/week
  • 39. Clinical Profile Age: 65 BMI: 32 Blood Glucose Last A1C: 10.2% PPG after lunch: 354 mg/dL Lipid Profile Total: 153 mg/dL LDL: 70 mg/dL HDL: 41 mg/dL Triglycerides: 225 mg/dL Kidney Profile Creatinine: 0.8 mg/dL Microalbuminuria: Negative Liver Function ALT: normal AST: normal Blood Pressure Normal: 130/90 mmHg Cardiovascular condition Previous myocardial infarction Eye Exam Normal Foot Exam Normal pulses and sensation
  • 40. Two questions that may be relevant 1. Add one injection of rapid acting insulin to basal insulin or switch to premix? 2. How should I think about increasing dose frequency?
  • 42. • Does insulin Initiation Guarantee Good Glycaemic Control ?
  • 43. Insulin initiation does not necessarily result in HbA1c reduction.  UK: 73% of patients maintained an HbA1c ≥7.5%, 6-months post insulin initiation1 Insulin treatment does not necessarily result in achieving goal HbA1c.  The INITIATE study, a 28-week parallel designed, randomized study, showed that 40% of patients on basal therapy and 66% of patients on premix achieved the target HbA1c of <7%2  The Treat to Target trial (4T) reported that 42% of patients adding basal insulin to oral therapy did not reach an HbA1c ≤7%3  The International Diabetes Management Practice Study (IDMPS), listed attainment of HbA1c goal (<7%) in patients with type 2 diabetes to be 37% (Asia), 36% (Eastern Europe), and 36% (Latin America) among patients treated with insulin4 Insulin Initiation Does Not Guarantee Good Glycaemic Control INITIATE = Initiate Insulin by Aggressive Titration and Education. 1. Calvert MJ, et al. Br J Gen Pract. 2007;57(539):455-460. 2. Raskin P, et al. Diabetes Care. 2005;28(2):260-265. 3. Riddle MC, et al. Diabetes Care. 2003;26(11):3080-3086. 4. Chan JC, et al. Diabetes Care. 2009;32(2):227-233.
  • 44. Basal insulin only (usually with oral agents) Non-insulin regimens Basal insulin + 1 (mealtime) rapid- acting insulin injection Premixed insulin twice daily Basal insulin + ≥2 (mealtime) rapid- acting insulin injections low mod. high 1 2 3+ Number of injections Regimen complexity More flexible Less flexible Flexibility Therapy following Basal Only Insulin Inzucchi SE, et al. Diabetes Care. 2012;35(6):1364-1379. If Basal insulin fails, what is the next best approach?
  • 45. IDF Treatment Algorithm for People with Type 2 Diabetes DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; TZD = thiazolidinedione. DF. Available at: http://www.idf.org/sites/default/files/IDF%20T2DM%20Guideline.pdf. Accessed 29 August 2013 Then, at each step, if not to target (generally HbA1c <7.0%) Consider first line Basal + mealtime insulin Consider second line Consider third line Consider fourth line Basal insulin, or premixed insulin (later basal + mealtime) or Basal insulin or Premixed insulin or AGI or DPP-4 inhibitor or TZD GLP-1 receptor agonist or Metformin (if not first time) AGI or DPP-4 inhibitor or TZDSulfonylurea Metformin Sulfonylurea or AGI Usual approach Alternative approach Lifestyles measures If Basal insulin fails, what is the next best approach?
  • 46. Second-line insulin choices in type 2 diabetes: patient factors Basal-bolus Premix Basal plus Patient preference for fewest injections + + Variable meal pattern + + Variable daily routine + Limited capability (eg, cognitive function, dexterity) + Better postprandial control required + + Unwilling to self-monitor several times daily + Limited support (family, general practitioner) + + Reference: Modified from Barnett A et al. Int J Clin Pract. 2008; 62:1647-1653
  • 47. • Humalog Mix50 – mimics physiological insulin secretion to provide tighter PPG control
  • 48. In Non-diabetic Individuals, Basal Secretion Represents Approximately 50% Total Daily Insulin Data from Polonsky KS et al. J Clin Invest 1988; 81:442-48 Normal Obese Extrapolated Basal Secretion 50.1±3.1% Normal subjects 45.2±2.2% Obese subjects 0 100 200 300 400 500 600 PercentBasalInsulinSecretion 0600 1000 1400 1800 2200 0200 0600 Clock Hours
  • 49. * After a test meal. Data derived from: Schwartz S, et al. Clin Ther. 2006;28:1649-1657. Schwartz S, et al. Diabetologia 2003;46(suppl 2):A267. Humalog® Mix50™ Tight Mealtime Control Increasing the proportion of rapid-acting insulin improves PPG* • PPG decreased as proportion of rapid-acting insulin increased • Basal-only insulin was associated with highest PPG of the 4 regimens 2-hrPPG(mmol/L) Each regimen resulted in PPG significantly different from all other regimens (pairwise comparison). P<0.05. Glargine Human Insulin 30/70 Humalog® Mix25™ Humalog® Mix50™ Patients without diabetes
  • 50. Humalog Mix50 injected three times daily comparison with human insulin 30/70
  • 51. Metabolic control in patients with type 2 diabetes using Humalog Mix50 injected three times daily: crossover comparison with human insulin 30/70 • Objectives – This study was designed to compare metabolic control with three daily injections of Humalog Mix50 or premixed human insulin 30/70 (30% regular/70% NPH) twice daily in accordance with normal prescription practice • Patients and methods – The study cohort of 40 patients with type 2 diabetes used a two- way, crossover design. Patients were randomized to either Mix50 at each main meal or human insulin 30/70 at breakfast and dinner for 3 months, followed by the alternate treatment for 3 months – Blood glucose was measured by the patients at baseline and at the end of each treatment sequence – No significant carryover effects were observed, so treatment sequences were combined and data analyzed by unpaired t-tests Schernthaner G et al. Horm Metab Res. 2004; 36: 188-193.
  • 52. LM50 TID vs. Humulin 30/70 BID: endpoint A1C LM50=50% insulin lispro/50% insulin lispro protamine suspension; Humulin 30/70=30% regular human insulin/70% human insulin isophane suspension. MeanA1C(%) 6.0 7.0 8.0 9.0 LM50 TIDHumulin 30/70Baseline p<0.001 8.4% 8.1% 7.6% p=0.021p=0.034 6.5 7.5 8.5 Schernthaner G et al. Horm Metab Res. 2004; 36: 188-193.
  • 53. 2-hour postprandial reductions in postprandial glucose were significantly greater with LM50 TID than those observed in Humulin 30/70 treatment (p0.001) *p<0.001 compared to baseline and Humulin 30/70. N=35 patients with type 2 diabetes mellitus. 24-week crossover. LM50=50% insulin lispro/50% insulin lispro protamine suspension; Humulin 30/70=30% regular human insulin/70% human insulin isophane suspension. Postprandialblood glucose(mmol/L) 6 8 10 12 After dinnerAfter lunchAfter breakfast LM50 TID Humulin 30/70 Baseline * * Schernthaner G et al. Horm Metab Res. 2004; 36: 188-193.
  • 54. Metabolic control in patients with type 2 diabetes using Humalog Mix50 injected three times daily: crossover comparison with human insulin 30/70 Study summary and conclusions – The decrease from baseline in A1C was significantly greater with Mix50 than with 30/70 insulin – There were no significant differences between treatments regarding incidence of hypoglycemia or adverse events – In patients with type 2 diabetes, a regimen of Humalog Mix50 administered three times daily before meals maintains glucose control more effectively than premixed human insulin 30/70 administered before breakfast and dinner Schernthaner G et al. Horm Metab Res. 2004; 36: 188-193.
  • 55. Two questions that may be relevant 1. Add one injection of rapid acting insulin to basal insulin or switch to premix? 2. How should I think about increasing dose frequency?
  • 56. Basal insulin only (usually with oral agents) Non-insulin regimens Basal insulin + 1 (mealtime) rapid- acting insulin injection Premixed insulin twice daily Basal insulin + ≥2 (mealtime) rapid- acting insulin injections low mod. high 1 2 3+ Number of injections Regimen complexity More flexible Less flexible Flexibility Therapy following Basal Only Insulin Inzucchi SE, et al. Diabetes Care. 2012;35(6):1364-1379. How can you add prandial insulin?
  • 57. AUTONOMY: The First Randomized Trial Comparing Two Patient-driven Approaches to Initiate and Titrate Prandial Insulin Lispro in Type 2 Diabetes Steve V. Edelman,1 Rong Liu,2 Jennal Johnson,2 Leonard C. Glass2 1University of California, San Diego Department of Medicine; 2Eli Lilly and Company, Indianapolis, IN, USA Edelman et al. Diabetes Care 2014;(Ahead of print).
  • 58. AUTONOMY: Study Objective • To compare efficacy and safety of 2 patient-based self-titration algorithms for initiation and titration of prandial insulin lispro in patients with type 2 diabetes inadequately controlled on basal insulin plus OADs in endocrine and generalist settings • Monitoring was done every day or every 3 days – Approximately 44% of trial sites were in primary care settings • 1st comparison of 2 self-titration insulin algorithms for escalation of prandial insulin lispro therapy in a large, multicountry, randomized, controlled trial Edelman et al. Diabetes Care 2014;(Ahead of print).
  • 59. AUTONOMY: Study Design Discontinue HbA1c ≤7.0% (≤53.0 mmol/mol) Randomize Enrollment Add insulin lispro 1-2-3 with adjustments (Q1D) Add insulin lispro 1-2-3 with adjustments (Q3D) NO 6 Weeks 24 Weeks Visit: 1 (screening) 2a 3a 4a,b 5a,b 6a 7a 8b 9b 10 11b 12 13b 14b 15 16b 17 18b 19 Week: -1 0 1 2 4 6 7 8 9 10 12 14 16 18 19 23 27 29 31 a6-week GLA optimization lead-in only required for subjects who had to be converted to GLA from insulin NPH, ILPS, or detemir; required conversion from GLA twice daily to once daily; or those on once-daily GLA at study entry with HbA1c >7.0% (>53.0 mmol/mol) and fasting blood glucose >120 mg/dL (>6.7 mmol/L). Subjects who did not require GLA optimization were randomized at Visit 2, forewent Visits 3 to 7 and instead proceeded to the randomized treatment period beginning with Visit 8 activities, 1 week after Visit 2; bTelephone visits Optional: Insulin Glargine (GLA) Optimization Lead-ina YES Edelman et al. Diabetes Care 2014;(Ahead of print).
  • 60. AUTONOMY: Primary and Secondary Outcome Measures • Primary efficacy outcome: – Compare change in HbA1c from baseline to endpoint (Week 24 after randomization) for Q1D and Q3D algorithms • Secondary outcomes: – Incidence and annualized rate of self-reported total, severe, and nocturnal hypoglycemia – Proportion of subjects achieving target values HbA1c ≤7.0% – Change in FBG, 7-point SMBG profile, and weight from baseline – Change in dose of basal (GLA) and prandial (lispro) insulin at end of study – Change in 1,5-anhydroglucitol (a marker of hyperglycemia) • Assessments in subjects ≥65 years of age: – Change in HbA1c, hypoglycemia (incidence and rate), FBG, and proportion of subjects achieving target • Safety was monitored throughout the study (hypoglycemia was considered an AE with severe hypoglycemia recorded as an SAE) Edelman et al. Diabetes Care 2014;(Ahead of print).
  • 61. AUTONOMY: Proportion Achieving HbA1c ≤7.0% *p<0.05 for Q3D vs. Q1D; p-values were computed based upon a logistic regression model with effects for treatment algorithms and strata Study A (N=528) Study B (N=578) p=0.015p=0.162p=0.701p=0.128 * Edelman SV. Diabetes Care 37:2132-40, 2014
  • 62. AUTONOMY: Change From Baseline Weight *p<0.05 for Q3D vs. Q1D; data were reported as LSM ± SE of the mean based upon from a MMRM that included baseline weight, strata, treatment algorithm, visit, and treatment algorithm by visit Weight(kg)ChangefromBaseline (LSM±SE) p=0.014 p=0.108 * Edelman SV. Diabetes Care 37:2132-40, 2014
  • 63. AUTONOMY: Discussion (Slide 1 of 2) • Both algorithms (Q1D, Q3D) demonstrated statistically significant and clinically equivalent reductions in HbA1c, significant increases in 1,5-AG, and improved 7-point SMBG profiles in Studies A and B • ~50% of subjects who had previously failed to reach goal HbA1c of ≤7.0% (53.0 mmol/mol) with basal insulin optimization plus OADs achieved the ADA goals for glycemic control with less glucose variability • Sequential addition of prandial insulin lispro injections resulted in ~61% of subjects only requiring ≤2 doses rather than a full basal-bolus regimen (ie, simplifies treatment, could enhance therapy compliance) • Subjects gained 2-3 kg of weight, regardless of treatment algorithm, with the initiation of prandial insulin Edelman et al. Diabetes Care 2014;(Ahead of print).
  • 64. • Results show basal-bolus therapy can be initiated in the elderly without increased risk of hypoglycemia • Regardless of titration algorithm, improved metabolic control was accomplished with low incidences and rates of nocturnal and severe hypoglycemia in both the overall study population and the elderly subgroup (≥65 years of age) with initiation and escalation of lispro AUTONOMY: Discussion (Slide 2 of 2) Edelman et al. Diabetes Care 2014;(Ahead of print).
  • 65. Conclusions Putting it into Practice • Recognise that the challenges of diabetes management for patients require a patient-centred approach • Patient education in order to optimise the types of behavioural modifications that support effective self-care habits