Transcript Slides - Projects In Knowledge

Advances in Insulin Therapies for
the Treatment of T1DM and T2DM
Lawrence Blonde, MD, FACP, FACE
Director of the Ochsner Diabetes Clinical Research Unit
Ochsner Medical Center
New Orleans, Louisiana
Vivian A. Fonseca, MD, FRCP
Professor of Medicine
Chief, Section of Endocrinology
Tulane University
New Orleans, Louisiana
Insulin Treatment for
T1DM and T2DM
Overview of Current
Treatment Strategies
Lawrence Blonde, MD, FACP, FACE
Pharmacologic Therapies for Diabetes
• Oral antihyperglycemic drugs
• Insulin
– Basal (long-acting)
– Prandial (rapid-acting/mealtime)
• Newer approved therapies
– GLP-1RAs, DPP-4 inhibitors, SGLT2 inhibitors,
inhaled insulin, U300 glargine
• Emerging agents
Insulin in T1DM and T2DM
What Are the Differences?
• T1DM
–
–
–
–
All T1DM patients require insulin
Usually smaller insulin doses than T2DM
Difficulty in achieving appropriate 24-hour coverage
Insulin regimens
• Multiple-dose insulin
• Continuous subcutaneous insulin infusion/continuous glucose
monitoring systems
• T2DM
– Not all T2DM patients require insulin
– Overcoming reluctance to use insulin
– Effect of other concomitant antihyperglycemic drugs on insulin
Barriers and Challenges to Insulin Use
Patient Resistance to Initiation and
Intensification of Injectable Therapies
• Self-blame1,2
– Less with history of better adherence, less DM “stress”
• Avoidance of injections2
• Concerns of risk2
–
–
–
–
Hypoglycemia
Weight gain
Complexity of regimens
Misconceptions about complications
• Skepticism of efficacy1,2
• Negative impact on social life2
1. Peyrot M, et al. Diabetes Care. 2005;28:2673-2679. 2.Karter A, et al. Diabetes Care. 2010;33:733-735.
Clinician Barriers/Resistance
•
•
•
•
•
•
Complexity of training/availability of resources
Time factors
Resources (educators)
Fear of hypoglycemia
Weight gain
Age factors
Peyrot M, et al. Diabetes Care. 2005;28:2673-2679.
Pen Delivery of Insulin
•
•
•
•
•
Encourages multiple-dose insulin therapy
Adds convenience
Enhances flexibility in schedule
Reduces insulin waste
May improve accuracy of correct dosage
delivery
When to Consider Insulin in a Person
with Type 2 Diabetes
• When a combination of noninsulin antihyperglycemic
medications are unable to achieve glycemic targets1,2
• When noninsulin medications are associated with
unacceptable adverse effects 2
• Advanced hepatic or kidney disease1
• Special considerations (steroids, infection, pregnancy)
• Hyperglycemia in a hospitalized patient
• Presence of severe hyperglycemia*2
* Random glucose >300 mg/dL, A1C >10%, ketonuria, symptomatic polyuria/polydipsia, weight loss.
1. ADA Diabetes Care. 2014:37(suppl 1):S14-S80. 2.Nathan DM, et al. Diabetes Care. 2009;32,193-203.
Addition of GLP-1 RAs vs. Basal Insulin to
Multiple Oral Agents
Background Oral
Treatments
(N)
(Change in A1C
from Baseline)
Basal Insulin
(Change in A1C
from Baseline)
MET + SU1 (N = 535)
-1.1
-1.1
2−3 OADs2 (N = 235)
-1.3
-1.3
NS
MET + GLIM3 (N = 576)
-1.3
-1.1
.0015
MET ± SU4* (N = 456)
-1.5
-1.3
<.05
MET ± SU5† (N = 216)
-1.3
-0.9
<.0001
GLP-1RA
P Value
(GLP-1R vs
Insulin)
Noninferior
*≈ 70% on MET monotherapy background.
†≈ 70% on MET + SU background.
1. Heine R, et al. Ann Intern Med. 2005;143:559-569. 2. Davies M, et al. Diabetes Obes Metab. 2009;11:1153-1162.
3. Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055. 4. Diamant M, et al. Lancet. 2010;375:2234-2243; 5. Davies M, et al.
Diabetes Care. 2013;36:1368-1376.
AACE Algorithm for Adding Basal Insulin
• A1c<8%: TDD 0.1-0.2 U/kg; A1c >8%: TDD 0.2-0.3 U/kg
• Titrate every 2-3 days to reach glycemic goals
– Fixed regimen: Increase TDD by 2U
– Adjustable regimen:
• FPG >180: Increase by 20% TDD
• FPG 140-180: Increase by 10% TDD
• FPG 110-139: Increase by 1U
• If hypoglycemia, reduce TDD by
– BG<70 mg/dL: 10%-20%
– BG<40 mg/dL: 20%-40%
AACE Comprehensive Diabetes Management Algorithm – 2015; Garber AJ, et al. Endo Pract. 2015;21: In press.
Initiation and Adjustment of Insulin
Regimens—Basal Insulin (Analog or NPH)
ADA/EASD Position Statement
Abbreviation: NPH, neutral protamine Hagedorn.
With permission from Inzucchi SE, et al. Diabetes Care. 2015;38:140-149.
Advantages of Basal Insulin Analogs
Over Human NPH Insulin
• Longer-acting (up to 24 hours or more)1
– Supports once-daily administration for most
patients
– Less day to day variability
• Flatter time action profile with less peak in
activity1
– Lower risk of nocturnal and overall hypoglycemia1,2
• Less weight gain (insulin detemir/U300 Insulin
Glargine)2
1. Hirsch IB. N Engl J Med. 2005;352:174-183. 2. Monami M, et al. Diabetes Res Clin Pract. 2008;81:184-189.
Options When Basal Insulin + Oral
Antihyperglycemic Agents Do Not
Achieve Target Glycemia?
• Add GLP-1 receptor agonists (GLP-1 RA) or
DPP-4 inhibitor
• Add SGLT-2 inhibitor
• Substitute premix insulin
• Add bolus, mealtime (prandial) insulin
• Add inhaled technosphere insulin
Initiation and Adjustment of Insulin Therapy—
Prandial Insulin (Analog or Regular or Premix)
ADA/EASD Position Statement
With permission from Inzucchi SE, et al. Diabetes Care. 2015;38:140-149.
Noninsulin Treatments for
Postprandial Hyperglycemia
• GLP-1 RA (exenatide bid, liraglutide, albiglutide,
dulaglutide*)
– Injectable agents that enhance insulin secretion and inhibit
glucagon release, both in a glucose-dependent manner1,2-3
– Shorter-acting GLP-1 RAs have greater impact on PPG levels
while longer acting GLP-1RAs tend to have greater effect on
fasting plasma glucose levels3
– Associated weight2,3 and BP reduction2 and improved lipid
levels
*Has not been studied in combination with basal insulin.
1. Campbell JE, et al. Cell Metab. 2013;17:819-837. 2.Garber AJ. Diabetes Care. 2011;34(suppl 2):s279-s284.
3. Cross LB, Brunell S. Am J Pharm Benefits. 2013:5:e139-e150.
Noninsulin Treatments to Improve
Postprandial Glucose
• DPP-4 inhibitors (sitagliptin, linagliptin, saxagliptin,
alogliptin)1
– Oral agents with moderate A1C improvement, especially
when combined with metformin
– Weight neutral
– Adjustments for renal impairment except linagliptin
• SGLT2 Inhibitors (canagliflozin, dapagliflozin,
empagliflozin)2,3
– Oral antihyperglycemic agents
– Associated with reduced systolic BP/diastolic BP and weight
– Limited use in patients with significant chronic kidney disease
1. Deacon CF, Holst JJ. Expert Opin Pharmacother. 2013;14:2047-2058. 2. Yale J, et al. Diabetes Obes Metab. 2013;15:463-473. 3.
Ghosh RK, et al. J Clin Pharmacol. 2012;52:457-463.
However, many type 2 diabetes
patients will require the addition
of a prandial insulin
to achieve glycemic goals
When It May be Time to Initiate Prandial
Insulin Therapy in T2DM?
• Individual is not meeting glycemic targets on basal insulin1,2
– A1C still not at goal with ≈0.5 U/kg/day of daily basal insulin
– A1C not at goal despite target fasting plasma glucose (FPG) with
basal insulin
– FPG with basal insulin is at target, but PPG is persistently above goal
• Large glucose drops overnight or between meals (suggesting
excessive amounts of basal insulin)
• Nocturnal hypoglycemia1,2
• When further increases in basal insulin result in hypoglycemia
1. Inzucchi S, et al. Diabetes Care. 2012;35:1364-1379. 2. ADA. Practical Insulin: A Handbook for Prescribing Providers. 3rd ed. 2011:1-68.
Role for Premixed Insulin
• Advantages
– Both basal and prandial components in a single insulin
preparation
– Can cover insulin requirements through most of day
• Disadvantages
–
–
–
–
–
Not physiologic
Requires consistent meal and exercise pattern,
Cannot separately titrate individual insulin components 1
↑ risk for nocturnal hypoglycemia2,3
↑ risk for fasting hyperglycemia if basal component does not
last long enough3
– Often requires accepting higher A1C goal (<7.5% or ≤8%)2,3
1. Inzucchi S. et al. ADA, EASD Position Statement. Diabetes Care. 2012;35;1364-1379. 2. Janka HU, et al. Diabetes Care.
2005;28:254-259. 3. Fritsche A, et al. Diab Obes Metab. 2010;12:115-123.
Initiation and Adjustment of Insulin Therapy—
Prandial Insulin (Analog or Regular or Premix)
ADA/EASD Position Statement
With permission from Inzucchi SE, et al. Diabetes Care. 2015;38:140-149.
Adding Prandial Insulin to Basal
Therapy Further Improves HbA1C
Regimen
Glargine ± OAD (n = 384)
Glargine ± OAD + OD prandial
(n = 21)
Glargine ± OAD + BID prandial
(n = 116)
Glargine + OAD + >BID prandial (165)
Reduction in HbA1c (%)
-0.67*
-1.22†
-1.61*
-1.43*
*P <.001. †P = .004: baseline to endpoint change.
Abbreviations: BID, twice daily; OAD, oral antihyperglycemic drug; OD, once daily.
Davies M, et al. Diabetes Res Clin Pract. 2008 ;79:368-375.
Advantages of Rapid-Acting Insulin
Analogs Over Regular Human Insulin
• More rapid onset of action
– Facilitates more convenient mealtime
administration
– Offers potential for better postprandial glucose
control
• More rapid return to basal insulin levels
– Potentially less hypoglycemia
• Greater predictability
Hirsch IB. N Engl J Med. 2005;352:174-183.
All Type 1 diabetes patients require
insulin and are best treated with multiple daily
injections of insulin with the basal and prandial
components given separately or with
continuous subcutaneous insulin infusion
Glycemic target achievement for many
of these patients remains challenging
Meeting ADA A1C Targets
Enrollment
Current
100%
Mean HbA1C (%)
80%
A1CA1c
Goal
= <8.5%
Goal
62% 62%
60%
A1c
Goal
A1C Goal
=
= <8.0%
<8.0%
42% 41%
40%
A1c Goal =
<7.0%
A1c Goal = <7.0%
A1c Goal
= <7.5%
21%
20%
18%
23%
29%
31%
28%
30%
18%
0%
<6
6-<13
13-<18
Age (years)
T1D Exchange, 2014. Courtesy of Satish K. Garg, MD
18-<26
26-<50
≥50
Frequency of Nonsevere
Hypoglycemic Events*
Frequency
Daily to ~ once a week
Once a month to several
times a month
Only a few times a year
or
vary rarely
*US patients.
Brod M, et al. Value Health. 2011;14:665-671.
T1DM
T2DM
(% Patients) (% Patients)
64.5
23.5
24.9
34.9
12.0
40.2
Impact of Hypoglycemia
• Hypoglycemia is associated with reduced quality of life,
lower treatment satisfaction, poorer adherence, and
greater resource utilization1-3
• Fear of hypoglycemia reduces patient adherence and
may affect glycemic control4
1. Alvarez-Guisasola F, et al. Health Qual Life Outcomes. 2010;8:86. 2. Marrett E, et al. BMC Res Notes. 2011;4:251. 3. Williams S, et al.
Diabetes Res Clin Pract. 2011;91:363-370. 4. Leiter LA, et al. Can J Diabetes 2005;29:186-192.
Sensor-Augmented Insulin-Pump
Therapy in T1DM
• 485 patients with inadequately controlled T1DM
• Randomized to sensor-augmented pump (SAP)
therapy or multiple daily insulin injections (MDI)
• SAP patients achieved a greater HbA1C reduction vs
MDI at 3 months and sustained it over 12 months
– 3 months: SAP 7.3% vs MDI 8.0%
– 12 months: SAP 7.5% vs MDI 8.1%
• Rate of severe hypoglycemia (per 100 person years)
– SAP 13.31 vs MDI 13.48
Bergenstal RM, et al. N Engl J Med. 2010;363:311-320.
Insulin Omissions Due to Weight Concerns
• Intentional insulin omission is common in
approximately 20% of individuals1
• In a study of 70 adolescent females and 73 adolescent
males2
– 10.3% of the females reported skipping insulin
– 7.4% reported taking less insulin for weight control
• Unhealthy weight control practices, including insulin
omission, associated with
– Poorer metabolic control3
– Microvascular complications4
1. Peyrot M, et al. Diabetes Care. 2010;33:240-245. 2. Neumark-Sztainer D, et al. Diabetes Care. 2002;25:1289-1296. 3. Rodin G, et al.
Psychosomatics.1991;32:171-176. 4. Rydall AC, et al. N Engl J Med. 1997;336:18-54.
Review of Currently Available
Insulin Analogs
Pharmacokinetics, Efficacy, and Safety
Vivian A. Fonseca, MD, FRCP
Normal Daily Insulin Profile
100
Insulin
(U/mL)
B
L
D
80
60
40
20
0600 0800
1200
1800
Time of Day
Abbreviations: B, breakfast; L, lunch; D, dinner.
Polonsky KS, et al. N Engl J Med. 1988;318:1231-1239.
2400
0600
The Basal/Bolus Insulin Concept
• Basal insulin
– Suppresses glucose production between meals and overnight
– Nearly constant levels
– 50% of daily needs
• Bolus insulin (mealtime or prandial)
– Limits hyperglycemia after meals
– Immediate rise and sharp peak at 1 hour
– 10% to 20% of total daily insulin requirement at each meal
• Ideally, for insulin-replacement therapy, each component
should come from a different insulin with a specific profile
Limitations of Human NPH, Insulin Zinc,
and Insulin Zinc Suspension
• Do not mimic basal insulin profile
– Variable absorption
– Pronounced peaks
– Less than 24-hour duration of action
• Cause unpredictable hypoglycemia
– Major factor limiting insulin adjustments
– More weight gain
Insulin zinc = lente; insulin zinc suspension = ultralente.
Currently Available Basal Insulins
NPH Insulin
Insulin Detemir
Insulin Glargine
Human;
intermediateacting
Analog;
long-acting
Analog;
long-acting
Onset
2−4 hours
N/A
N/A
Peak
4−10 hours
Relatively flat
No pronounced
peak
Effective
duration
10−16 hours
Up to 24 hours
Up to 24 hours
Insulin type
Niswender K, et al. Clin Diabetes. 2009;27:60-68. Courtesy of Dr. Fonseca.
Glargine vs NPH Insulin in Type 1 Diabetes
Action Profiles by Glucose Clamp
Glucose Utilization Rate
(mg/kg/h)
6
5
4
NPH
3
2
Glargine
1
0
0
10
20
Time (h) after SC Injection
30
End of observation period
Abbreviations: NPH, neutral protamine Hagedorn; SC, subcutaneous.
With permission from Lepore M, et al. Diabetes. 2000;49:2142-2148.
Addition of Basal Insulin to Oral Therapy
Treat-to-Target Trial
9.0
A1C (%)
8.5
Glargine
NPH
8.0
7.5
7.0
6.5
6.0
0
4
8
12
16
20
Hypoglycemia
(Documented PG ≤56 mg/dL)
Glycemic Control
Over Time
Cumulative Number of Events
756 Patients with Type 2 Diabetes on 1 or 2 Oral Agents
900
800
700
600
500
400
300
200
100
24
Weeks of Treatment
0
0
24
48
96 120 144 168
Time (days)
Abbreviations: NPH, neutral protamine Hagedorn; PG, plasma glucose.
With permission from Riddle MC, et al. Diabetes Care. 2003;26:3080-3086.
72
Hypoglycemia
The Quest for a Better Basal Insulin…
A “Qualified A1C” by Hypoglycemia
~ 0.4–0.6% ?
NPH
Glargine
A1C
With permission from Rosenstock J, et al. J Diabetes Complications. 2014;28:742-749.
Prandial Insulins—Rapid-Acting Analogs
vs Regular Human Insulin
Lispro
Rapid Acting
Aspart
Glulisine
Regular
Human
Onset (h)
<0.3−0.5
0.25
0.25
0.5−1.0
Peak (h)
0.5−2.5
0.5−1.0
1.0−1.5
2.0−3.0
Duration (h)
3.0−6.5
3.0−5.0
3.0−5.0
3.0−6.0
Rapid-acting analogs have more rapid onset and shorter time to
peak than regular human insulin.
ADA Practical Insulin: A Handbook for Prescribing Providers. 3rd ed. 2011:1-68.
Insulin Analogs May Offset the Risk of
Hypoglycemia Often Observed with Insulin
Initiation in T2DM
Hypoglycemia
Analogs vs Human
Basal Insulin
(Odds Ratio)
Analogs vs Human
Prandial Insulin
(Odds Ratio)
All
0.71*
0.81
Nocturnal
0.41*
n/a
Severe
0.69
1.21
In contrast with other studies, this meta-analysis found that adding OADs to insulin
regimens increased the risk of nocturnal hypoglycemia despite lower insulin TDD,
but some included trials allowed SUs
Insulin doses, TDD: basal, 39 U; twice-daily, 50 U; prandial, 65 U.
*P <.05 within group.
Pontiroli AE, et al. Diabetes Obes Metab. 2012;14: 433-446.
The Need for New Insulin Therapies in
T1DM and T2DM
• New insulin formulations/combinations that
provide 24-hour coverage and may reduce
hypoglycemia
• New insulin formulations/combinations that
improve postprandial glycemic excursions
• New insulin therapies/delivery devices that are
easier and more convenient and that facilitate
patient adherence
Rapid-Acting Inhaled Human Insulin
Recently Approved
• Inhalation powder1
• Maximum concentration and peak effect occur sooner
vs regular human insulin or rapid-acting insulin
analogs2
• Must be used in combination with long-acting insulin
in patients with T1DM1,3
• Contraindicated in patients with chronic lung disease
due to risk of acute bronchospasm—assess for
potential lung disease before initiating1,3
• Not recommended in patients who smoke1,3
1. Nuffer W, et al. Ann Pharmacother. 2015;49: 99-106. 2. Boss A, et al. J Diabetes Sci Technol. 2012;6:773-779. 3. Technosphere PI. Sanofi-Aventis;
Bridgewater, NJ. October 2014.
Inhaled Insulin Compared with Inhaled Powder
Placebo in Insulin-Naive Type 2 Diabetes
Suboptimally Controlled with Oral Agents
Inhaled Insulin
Powder Placebo
P Value
A1C Mean Reduction (%)
Overall
-0.7
-0.3
.003
Mild to moderate
-0.5
-0.2
.05
Moderate to severe
-1.2
-0.4
.01
Week 0
4500
4500
Week 12
2000
4500
Postprandial Glucose
Excursion from Baseline
(min mg/dL)
Rosenstock J, et al. Diabetes Care. 2008;31:2177-2182.
Emerging Basal Insulin Analogs
Lawrence Blonde, MD, FACP, FACE
Basal Insulin Analogs:
Newly approved or in Development
• Insulin glargine U300: FDA approved 2/25/15
• Insulin degludec U100 and U200
• Pegylated insulin lispro
Basal Insulins in Development
High Concentration Glargine (U300)*
• Highly concentrated insulin with reduced rate
of absorption1
• Flatter, prolonged pharmacokinetic and
pharmacodynamic profiles and more
consistency2,3
• Half-life is ~23 h, duration 36 h, steady state 4
days3
*FDA approved February 25, 2015.
1. Garber AJ. Diabetes Obesity Metab. 2014;16:483-491. 2. Owens DR, et al. Diabetes Metab Res Rev. 2014;30:104-119.
3. Steinstraesser A, et al. Diabetes Obes Metab. 2014;16:873-876.
Glargine-Based
U300 glargine: FDA approved
2/25/15
• T2DM1
– Similar Δ A1C (−1.0%)
– Lower hypoglycemia risk
(RR, 0.92; 95% CI, 0.87−0.96)
• T1DM2
– Noninferior Δ A1C
– Similar hypoglycemia
– Significantly less weight gain
• Flatter, longer PK/PD profile
than U100 glargine3
LY2963016 (glargine
biosimilar): submitted to
FDA—stay of approval
• Sequence identical to
GLAR
• Similar, significant Δ A1C
(noninferiority) compared
with GLAR4,5
• No differences in
secondary efficacy or
safety outcomes,
including hypoglycemia4,5
1. Ritzel R, et al. ADA 74th Scientific Sessions. 2014;90-LB. 2. Home R, et al. ADA 74th Scientific Sessions. 2014;80-LB. 3. Tillner J, et al.
ADA 73rd Scientific Sessions. 2013;920-P. 4. Rosenstock J, et al. ADA 74th Scientific Sessions. 2014;64-OR. 5. Blevins T, et al. ADA 74th
Scientific Sessions. 2014;69-OR.
Insulin Degludec*
• desB30 insulin acylated (16-c fatty acid chain) at
LysB29
• Half-life is ~24 hours, duration >42 hours, steady state
2−3 days
• Smooth and stable pharmacokinetic profile at steady
state
• Longer action profile than current basal insulin
formulations
• Lower within-subject variability
• FDA withheld approval in 2013, research ongoing
*Not FDA approved.
Garber AJ. Diabetes Obesity Metab. 2014;16:483-491.
Insulin Degludec*
• FDA resubmission pending cardiovascular outcomes
study
• Similar Δ A1C, and Δ weight when compared with
GLAR1,2
– T2DM
• Lower nocturnal confirmed and/or overall confirmed and/or severe
hypoglycemia (P <.05)1, 4, 5
– T1DM
• Lower nocturnal hypoglycemia (P <.05)2
– Longer, less variable PK/PD profile than U100 glargine3
*Not FDA approved.
1. Rodbard H, et al. Diabet Med. 2013;30:1298-1304. 2. Bode B, et al. Diabet Med. 2013;30:1293-1297. 3. Garber A. Diabetes Obes
Metab. 2014;16:483-491. 4. Garber, A. J., et al. (2012). Lancet 379(9825): 1498-1507. 5. Ratner, R. E., et al. (2013). Diabetes, obesity
& metabolism 15(2): 175-184.
Pegylated Insulin Lispro*
• Polyethylene glycol polymer attached to
lispro1,2
• Half-life is 2−3 d,1,2 duration >36 h,1,2
steady state 7−10 d3
• Hepatic action1,4: May benefit weight,4 ↓gluc,
postprandial4
• Development postponed: Awaiting additional
study results
*Not FDA approved.
1. Garber AJ. Diabetes Obesity Metab. 2014;16:483-491. 2. Owens DR, et al. Diabetes Metab Res Rev. 2014;30;104-119.
3. Madsbad S. Diabetes. 2014;63:390-392. 4. Henry RR et al. Diabetes Care. 2014;37:2609-2615.
Pegylated Lispro vs Glargine in Adults
with T2DM at 12 Weeks
• Patients with T2DM, 12 weeks
• After adjusting for baseline rates, nocturnal hypoglycemia was
48% lower in the pegylated lispro group (P = .021)
Outcome
PEGL QD
(n = 195; 0.59 U/kg)
GLAR QD
(n = 93; 0.60 U/kg)
P Value
∆ A1C, %
‒0.7
‒0.7
NS
∆ Weight, kg
‒0.6
0.3
.001
Overall hypoglycemia, EPY
1.3
1.5
.804
Nocturnal hypoglycemia, EPY
0.3
0.4
.178
0
0
Severe hypoglycemia, number of
episodes
Abbreviations: EPY, events/patient-year; GLAR, insulin glargine; PEGL, pegylated insulin lispro; QD, once daily.
2-period, phase II randomized trial.
Pegylated insulin lispro is not FDA approved for clinical use.
Hypoglycemia, plasma glucose ≤70 mg/dL or severe per ADA definition.
Bergenstal RM, et al. Diabetes Care. 2012;35:2140-2147. Courtesy of Dr. Fonseca.
Pegylated Lispro vs Glargine in Adults with T2DM
at 12 Weeks—Other Phase II Safety Outcomes
Glargine
PEGlispro
Glargine Baseline
PEGlispro 12 Weeks
Glargine 12 Weeks
Triglycerides
Triglycerides
PEGlispro Baseline
20
40
60
0
80 100 120 140 160 180
mg/dL
20
40
60
80 100 120 140 160 180
mg/dL
AST
AST
ALT
ALT
0
0
10
20
30
40
U/L
• Number of patients: PEGL (n = 195), GLAR (n = 93).
• Pegylated insulin lispro is not FDA approved for clinical use.
Bergenstal RM, et al. Diabetes Care. 2012;35:2140-2147.
0
10
20
U/L
30
40
Emerging Prandial Insulin Analogs
Vivian A. Fonseca, MD, FRCP
Ideal Prandial Insulin
Desirable
Characteristics
Predictable
time-action
profile
Benefits
Precise dosing
Improve postmeal
Rapid onset of
action
Reduced risk of
hypoglycemia (day
and night)
Short duration
of action
Less weight gain
Approaches to Accelerate the Time Action
Profiles of Fast-Acting Insulins
• Faster insulins
– Rapid release, modified recombinant human insulin (Phase III)
– Ultra-rapid insulin lispro (Phase II)
– Faster-acting aspart (Phase III)
• Coformulation with hyaluronidase (Phase IV)
• Warming the infusion site
• Alternate routes
– Inhaled Insulin (FDA approved)
– Intradermal
– Intraperitoneal
Faster Aspart in T1DM Patients
• Appeared more rapidly and achieved higher early
exposure than insulin aspart1
• Greater early glucose-lowering effect in patients with
T1DM1
• 33% improvement in postprandial glucose, compared
with insulin aspart (Phase I study)
• Phase III trials are under way to assess efficacy and
safety of faster aspart
1. Haahr H, et al. EASD 2014 Annual Meeting, Vienna, Austria, Sept 15-19. ePoster #936.
Ultra-Rapid Insulin Lispro
• Earlier onset of action, stronger metabolic effect, and
greater insulin lispro exposure in the first 2 hours than
insulin lispro
• Significantly lower exposure and metabolic effect after
3 hours than insulin lispro
• Has the potential to be injected at mealtime or
postprandially and to improve postprandial glycemic
control, compared with available bolus insulin
Andersen G, et al. EASD 2014 Annual Meeting, Vienna, Austria, Sept 15-19. ePoster #934.
Rapid-Acting Insulin Analogs
Combinations with Hyaluronidase
• Hyaluronidases increase the dispersion and absorption
of subcutaneously administered drugs1,2
• Accelerates the absorption and action of coinjected
regular human insulin and the rapid-acting insulin analog
lispro1
• Produces earlier and greater peak insulin concentrations,
leading to improved postprandial glycemic control1
• No increased injection site pain, erythema or induration,
and no other increased adverse effects1
1. Hompesch M, et al. Diabetes Care. 2011;34:666-668. 2. Vaughn DE et al. Diabetes Technol Ther. 2009;11:345-352.
Coadministration of Prandial Insulins
with Hyaluronidase
• Early insulin exposure (0−60 min)
– rHuPH20 + lispro vs lispro: +54% (P = .0011)
– rHuPH20 + RHI vs RHI: +206% (P >.0001)
• Peak blood insulin
– rHuPH20 + lispro vs lispro: -26 mg/dL (P = .002)
– rHuPH20 + RHI: -24 mg/dL (P = .017)
• Reduced hypoglycemic excursions
– rHuPH20 + lispro vs lispro: -79% (P = .09)
– rHuPH20 + RHI vs RHI: -85% (P = .049)
Abbreviations: rHuPH20, recombinant human hyaluronidase; RHI, regular human insulin.
Hompesch M, et al. Diabetes Care. 2011; 34:666-668.
Smart Insulin
Self-Regulation of Insulin Based on Glycemic Levels
• All types of smart insulin require 2 components:
A glucose sensor and an insulin delivery device
• Nano-plugs
– Cross-linked bovine serum albumin, glucose oxidase and
catalase enzymes, pH response hydrogel particles and
multifunctional manganese dioxide nanoparticles bound to
insulin reservoir
– Plug detects glucose levels, leading to enzymatic catalysis of
insulin nanoparticles and release of insulin
• Other nano-based smart insulins: microgel; nanonetworks
Kalra S. J Pak Med Assoc.2014;64:95-97.
Combination Insulin Therapies in
Development
Vivian A. Fonseca MD, FRCP
Insulin Degludec/Liraglutide,* a Fixed Ratio
Combination in Patients with T2DM
Results of a Large, Randomized, Phase III Trial
IDegLira vs
IDeg
Estimate
[95% CI]
P-value
IDegLira vs
Lira
Estimate
[95% CI]
P-value
A1C change
(%-points)
−0.47
[−0.58; −0.36]
<.0001
−0.64
[−0.75; −0.53]
<.0001
FPG change
(mg/dL)
−3.1
[−7.4; 1.2]
NS
−31.8
[−36.1; −27.5]
<.0001
−2.22
[−2.64; −1.80]
<.0001
2.44
[2.02; 2.86]
<.0001
Weight change
(kg)
The primary endpoint, A1C, decreased by 1.9% from 8.3% to 6.4% with IDegLira.
This decrease was greater than with IDeg (-1.4% to 6.9%) or Lira (-1.3% to 7.0%).
*Not FDA approved.
Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2:885-893. Courtesy of Dr. Fonseca.
PK and PD Characteristics of a Fixed
Combination of Glargine and Lispro
PK/PD Characteristic
Fixed Combo
(75% glargine/
25% lispro)
Lispro
Onset of action
25 min
40 min
Tmax
2.8 h
3.4 h
AUCGIR (0−2 h)
504 mg/kg
325 mg/kg
AUCPK (0−1 h)
86 h*m/UL
34 h*m/UL
AUCGIR (12−30 h)
1480 mg/kg
961 mg/kg
AUCPK (12−30 h)
563 h*m/UL
286 h*m/UL
Duration (time to BG >118 mg/dL)
29.8 h
25.5 h
Half-life
17.6 h
7.7 h
Hovelmann U, et al. 2014 ADA Annual Meeting. June 13-17; San Francisco, CA. 83-LB.
P<.05, all
comparisons
Summary
• All type 1 and many type 2 diabetes patients
require insulin for glycemic control
• Whether basal insulin or a GLP-1 receptor
agonist should be the 1st injectable should be
individualized
• Insulin analogs, such as glargine, detemir, lispro,
and aspart, have several advantages over
human insulin products
Summary
• When FPG is at goal but A1C is elevated, PPG needs to be
assessed
• Multiple options for addressing elevated PPG in T2DM, but
ultimately many patients may require prandial insulin
• At present, using separate basal and prandial insulins has
advantages over premixed insulins
• New basal and prandial insulin analogs are in
development, including glargine U300*, degludec, and
pegylated insulin lispro, as well as new insulin analog
combination products and combinations of insulin and
noninsulin therapies
*FDA approved 2/25/15.
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