Advances in Insulin Therapies for the Treatment of T1DM and T2DM Lawrence Blonde, MD, FACP, FACE Director of the Ochsner Diabetes Clinical Research Unit.

Advances in Insulin Therapies for the Treatment of T1DM and T2DM

Lawrence Blonde, MD, FACP, FACEDirector of the Ochsner Diabetes Clinical Research Unit

Ochsner Medical CenterNew 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 T2DMWhat 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

1. ADA Diabetes Care. 2014:37(suppl 1):S14-S80. 2.Nathan DM, et al. Diabetes Care. 2009;32,193-203.

* Random glucose >300 mg/dL, A1C >10%, ketonuria, symptomatic polyuria/polydipsia, weight loss.

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 A1Cfrom Baseline)

P Value(GLP-1R vs

Insulin)MET + SU1 (N = 535) -1.1 -1.1 Noninferior

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

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.

*≈ 70% on MET monotherapy background.†≈ 70% on MET + SU background.

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

With permission from Inzucchi SE, et al. Diabetes Care. 2015;38:140-149.

Abbreviation: NPH, neutral protamine Hagedorn.

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

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.

*Has not been studied in combination with basal insulin.

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 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. 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

<6 6-<13 13-<18 18-<26 26-<50 ≥500%

20%

40%

60%

80%

100%

62%

42%

21% 23%29% 28%

62%

41%

18% 18%

31% 30%

Enrollment Current

Age (years)

Mea

n Hb

A1C

(%)

A1c Goal

= <8.0

%

A1c Goal

A1c Goal = <7.0%

A1c Goal = <7.0%

A1C Goal = <8.0%

A1C Goal = <8.5%

A1c Goal = <7.5%

T1D Exchange, 2014. Courtesy of Satish K. Garg, MD

Meeting ADA A1C Targets

Frequency of Nonsevere Hypoglycemic Events*

Frequency T1DM(% Patients)

T2DM(% Patients)

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

Brod M, et al. Value Health. 2011;14:665-671.

*US patients.

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

Polonsky KS, et al. N Engl J Med. 1988;318:1231-1239.

Normal Daily Insulin Profile

Abbreviations: B, breakfast; L, lunch; D, dinner.

0600 0600

Time of Day

20

40

60

80

100 B L D

0600 0800 18001200 2400 0600

Insulin(U/mL)

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

Niswender K, et al. Clin Diabetes. 2009;27:60-68. Courtesy of Dr. Fonseca.

NPH Insulin Insulin Detemir Insulin Glargine

Insulin typeHuman;

intermediate-acting

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

Glargine vs NPH Insulin in Type 1 DiabetesAction Profiles by Glucose Clamp

With permission from Lepore M, et al. Diabetes. 2000;49:2142-2148.

6

5

4

3

2

1

00 10

Time (h) after SC Injection

End of observation period

20 30

Glargine

NPH

Glu

cose

Util

izati

on R

ate

(mg/

kg/h

)

Abbreviations: NPH, neutral protamine Hagedorn; SC, subcutaneous.

Addition of Basal Insulin to Oral Therapy Treat-to-Target Trial

756 Patients with Type 2 Diabetes on 1 or 2 Oral Agents

With permission from Riddle MC, et al. Diabetes Care. 2003;26:3080-3086.

NPHGlargine

9.0

8.5

8.0

7.5

7.0

6.5

6.0

A1C

(%

)

0 4 8 12 16 20 24

Cu

mu

lati

ve N

um

ber

of

Eve

nts

(D

ocu

men

ted

PG

≤56

mg

/dL

)

Weeks of Treatment Time (days)

900

800

600

500

300

100

0

700

400

200

0 24 48 72 96 120 168144

Glycemic Control Over Time

Hypoglycemia

Abbreviations: NPH, neutral protamine Hagedorn; PG, plasma glucose.

Hyp

og

lyce

mia

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;28:742-749.

Prandial Insulins—Rapid-Acting Analogs vs Regular Human Insulin

Rapid Acting Lispro Aspart Glulisine

Regular Human

Onset (h) <0.3−0.5 0.25 0.25 0.5−1.0Peak (h) 0.5−2.5 0.5−1.0 1.0−1.5 2.0−3.0Duration (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 HumanBasal 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

Postprandial Glucose Excursion from Baseline(min mg/dL) Week 0 4500 4500

Week 12 2000 4500

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

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.

*FDA approved February 25, 2015.

Glargine-BasedU300 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

Garber AJ. Diabetes Obesity Metab. 2014;16:483-491. *Not FDA approved.

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

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.

*Not FDA approved.

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

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.

*Not FDA approved.

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)

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.

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

Severe hypoglycemia, number of episodes 0 0

Bergenstal RM, et al. Diabetes Care. 2012;35:2140-2147. Courtesy of Dr. Fonseca.

Trig

lyce

ride

s

0 20 40 60 80 100 120 140 160 180

GlargineGlargine Baseline Glargine 12 Weeks

mg/dL

AST

ALT

0 10 20 30 40

U/L

Trig

lyce

ride

s

0 20 40 60 80 100 120 140 160 180

PEGlisproPEGlispro Baseline PEGlispro 12 Weeks

mg/dL

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;35:2140-2147.

AST

ALT

0 10 20 30 40

U/L

Emerging Prandial Insulin Analogs

Vivian A. Fonseca, MD, FRCP

Ideal Prandial Insulin

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

Desirable Characteristics Benefits

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)

Hompesch M, et al. Diabetes Care. 2011; 34:666-668.

Abbreviations: rHuPH20, recombinant human hyaluronidase; RHI, regular human insulin.

Smart InsulinSelf-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-networksKalra 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 TrialIDegLira vs

IDegEstimate [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

Weight change (kg)

−2.22 [−2.64; −1.80] <.0001 2.44

[2.02; 2.86] <.0001

Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2:885-893. Courtesy of Dr. Fonseca.

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.

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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