1. 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

2. Insulin Treatment for T1DM and T2DM Overview of Current Treatment Strategies Lawrence Blonde, MD, FACP, FACE

3. 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

4. Insulin in T1DM and T2DM What Are the Differences?
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

5. Barriers and Challenges to Insulin Use

6. 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: Karter A, et al. Diabetes Care. 2010;33:

7. 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:

8. 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

9. 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,

10. Addition of GLP-1 RAs vs. Basal Insulin to Multiple Oral Agents
Background Oral Treatments
(N)
GLP-1RA
(Change in A1C from Baseline)
Basal Insulin
(Change in A1C
from Baseline)
P Value
(GLP-1R vs Insulin)
MET + SU1 (N = 535)
-1.1
Noninferior
2−3 OADs2 (N = 235)
-1.3 NS
MET + GLIM3 (N = 576)
.0015
MET ± SU4* (N = 456)
-1.5
<.05
MET ± SU5† (N = 216)
-0.9
<.0001
*≈ 70% on MET monotherapy background.
†≈ 70% on MET + SU background.
Heine R, et al. Ann Intern Med. 2005;143: Davies M, et al. Diabetes Obes Metab. 2009;11:
3. Russell-Jones D, et al. Diabetologia. 2009;52: Diamant M, et al. Lancet. 2010;375: ; 5. Davies M, et al.
Diabetes Care. 2013;36:

11. AACE Algorithm for Adding Basal Insulin
A1c<8%: TDD U/kg; A1c >8%: TDD 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 : Increase by 10% TDD
FPG : 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.

12. 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:

13. 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: Monami M, et al. Diabetes Res Clin Pract. 2008;81:

14. Add GLP-1 receptor agonists (GLP-1 RA) or DPP-4 inhibitor
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 14

15. 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:

16. 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: Garber AJ. Diabetes Care. 2011;34(suppl 2):s279-s Cross LB, Brunell S. Am J Pharm Benefits. 2013:5:e139-e150.

17. 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: Yale J, et al. Diabetes Obes Metab. 2013;15: Ghosh RK, et al. J Clin Pharmacol. 2012;52:

18. However, many type 2 diabetes patients will require the addition of a prandial insulin to achieve glycemic goals

19. 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: ADA. Practical Insulin: A Handbook for Prescribing Providers. 3rd ed. 2011:1-68.

20. 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; Janka HU, et al. Diabetes Care. 2005;28: Fritsche A, et al. Diab Obes Metab. 2010;12: 20

21. 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:

22. Adding Prandial Insulin to Basal Therapy Further Improves HbA1C
Regimen
Reduction in HbA1c (%)
Glargine ± OAD (n = 384)
-0.67*
Glargine ± OAD + OD prandial (n = 21)
-1.22†
Glargine ± OAD + BID prandial (n = 116)
-1.61*
Glargine + OAD + >BID prandial (165)
-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 ;79:

23. 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:

24. 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

25. Meeting ADA A1C Targets A1c Goal A1c Goal = <8.0%
= <8.5%
A1c Goal
A1c Goal = <7.0%
A1c Goal = <7.0%
A1c Goal
= <8.0%
A1C Goal
= <8.0%
A1c Goal
= <7.5%
T1D Exchange, Courtesy of Satish K. Garg, MD

26. Frequency of Nonsevere Hypoglycemic Events*
T1DM
(% Patients)
T2DM
Daily to ~ once a week
64.5
24.9
Once a month to several times a month
23.5
34.9
Only a few times a year or vary rarely
12.0
40.2
*US patients.
Brod M, et al. Value Health. 2011;14:

27. 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: Marrett E, et al. BMC Res Notes. 2011;4: Williams S, et al. Diabetes Res Clin Pract. 2011;91: Leiter LA, et al. Can J Diabetes 2005;29:

28. 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 vs MDI 13.48
Bergenstal RM, et al. N Engl J Med. 2010;363:

29. 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: Neumark-Sztainer D, et al. Diabetes Care. 2002;25: Rodin G, et al. Psychosomatics.1991;32: Rydall AC, et al. N Engl J Med. 1997;336:18-54.

30. Vivian A. Fonseca, MD, FRCP
Review of Currently Available Insulin Analogs Pharmacokinetics, Efficacy, and Safety
Vivian A. Fonseca, MD, FRCP

31. Normal Daily Insulin Profile
0600
Time of Day 20 40 60 80
100 B L D
0800
1800
1200
2400
Insulin
(U/mL)
Abbreviations: B, breakfast; L, lunch; D, dinner.
Polonsky KS, et al. N Engl J Med. 1988;318:

32. 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

33. 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.

34. Currently Available Basal Insulins
NPH Insulin
Insulin Detemir
Insulin Glargine
Insulin type
Human;
intermediate-acting
Analog;
long-acting
Onset
2−4 hours
N/A
Peak
4−10 hours
Relatively flat
No pronounced peak
Effective duration
10−16 hours
Up to 24 hours
Niswender K, et al. Clin Diabetes. 2009;27: Courtesy of Dr. Fonseca.

35. Glucose Utilization Rate
Glargine vs NPH Insulin in Type 1 Diabetes Action Profiles by Glucose Clamp 6 5 4 3 2 1 10
Time (h) after SC Injection
End of observation period 20 30
Glargine
NPH
Glucose Utilization Rate
(mg/kg/h)
Abbreviations: NPH, neutral protamine Hagedorn; SC, subcutaneous.
With permission from Lepore M, et al. Diabetes. 2000;49:

36. Addition of Basal Insulin to Oral Therapy Treat-to-Target Trial
756 Patients with Type 2 Diabetes on 1 or 2 Oral Agents
NPH
Glargine
9.0
8.5
8.0
7.5
7.0
6.5
6.0
A1C (%) 4 8 12 16 20 24
Cumulative Number of Events (Documented PG ≤56 mg/dL)
Weeks of Treatment
Time (days)
900
800
600
500
300
100
700
400
200 48 72 96
120
168
144
Glycemic Control Over Time
Hypoglycemia
Abbreviations: NPH, neutral protamine Hagedorn; PG, plasma glucose.
With permission from Riddle MC, et al. Diabetes Care. 2003;26:
17/04/ :37

37. Hypoglycemia
NPH
Glargine
A1C
~ 0.4–0.6% ?
The Quest for a Better Basal Insulin… A “Qualified A1C” by Hypoglycemia
With permission from Rosenstock J, et al. J Diabetes Complications. 2014;28:

38. Prandial Insulins—Rapid-Acting Analogs vs Regular Human Insulin
Lispro Aspart Glulisine
Regular
Human
Onset (h)
<0.3−
0.5−1.0
Peak (h)
0.5− − −1.5
2.0−3.0
Duration (h)
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.

39. Analogs vs Human Prandial Insulin
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
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:

40. 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

41. 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: Boss A, et al. J Diabetes Sci Technol. 2012;6: Technosphere PI. Sanofi-Aventis; Bridgewater, NJ. October 2014.

42. 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
Postprandial Glucose
Excursion from Baseline
(min mg/dL)
Week 0
4500
Week 12
2000
Rosenstock J, et al. Diabetes Care. 2008;31:

43. Emerging Basal Insulin Analogs Lawrence Blonde, MD, FACP, FACE

44. Basal Insulin Analogs: Newly approved or in Development
Insulin glargine U300: FDA approved 2/25/15
Insulin degludec U100 and U200
Pegylated insulin lispro

45. 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: Owens DR, et al. Diabetes Metab Res Rev. 2014;30:
3. Steinstraesser A, et al. Diabetes Obes Metab. 2014;16:

46. 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
LY (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.

47. 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:

48. 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: Bode B, et al. Diabet Med. 2013;30: Garber A. Diabetes Obes Metab. 2014;16: Garber, A. J., et al. (2012). Lancet 379(9825): Ratner, R. E., et al. (2013). Diabetes, obesity & metabolism 15(2):

49. 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: Owens DR, et al. Diabetes Metab Res Rev. 2014;30;
3. Madsbad S. Diabetes. 2014;63: Henry RR et al. Diabetes Care. 2014;37:

50. 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 NS
∆ Weight, kg
‒0.6
0.3
.001
Overall hypoglycemia, EPY
1.3
1.5
.804
Nocturnal hypoglycemia, EPY
0.4
.178
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: Courtesy of Dr. Fonseca.

51. Pegylated Lispro vs Glargine in Adults with T2DM at 12 Weeks—Other Phase II Safety Outcomes
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:

52. Emerging Prandial Insulin Analogs Vivian A. Fonseca, MD, FRCP

53. Ideal Prandial Insulin
Desirable Characteristics
Benefits
Precise dosing
Improve postmeal
Reduced risk of hypoglycemia (day and night)
Less weight gain
Predictable time-action profile
Rapid onset of action
Short duration of action

54. 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

55. 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 ePoster #936.

56. 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 Annual Meeting, Vienna, Austria, Sept ePoster #934.

57. 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: Vaughn DE et al. Diabetes Technol Ther. 2009;11:

58. 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:

59. 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; nano-networks
Kalra S. J Pak Med Assoc.2014;64:95-97.

60. Combination Insulin Therapies in Development Vivian A. Fonseca MD, FRCP

61. IDegLira vs IDeg Estimate [95% CI] IDegLira vs Lira Estimate [95% CI]
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]
A1C change (%-points)
−0.47 [−0.58; −0.36]
<.0001
−0.64 [−0.75; −0.53]
FPG change (mg/dL)
−3.1 [−7.4; 1.2] NS
−31.8 [−36.1; −27.5]
Weight change (kg)
−2.22 [−2.64; −1.80]
2.44 [2.02; 2.86]
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: Courtesy of Dr. Fonseca.

62. 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
P<.05, all comparisons
Hovelmann U, et al ADA Annual Meeting. June 13-17; San Francisco, CA. 83-LB.

63. 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

64. 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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