Main Pathophysiological Defects in T2DM “The Ominous...

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Main Pathophysiological Defects in T2DM “The Ominous Octet” Islet β-cell Impaired Insulin Secretion Neurotransmitter Dysfunction Decreased Glucose Uptake Islet α-cell Increased Glucagon Secretion Increased Lipolysis Increased Glucose Reabsorption Increased HGP Decreased Incretin Effect Defronzo RA. Diabetes. 2009 Apr;58(4):773-95.

Transcript of Main Pathophysiological Defects in T2DM “The Ominous...

Main Pathophysiological Defects in T2DM “The Ominous Octet”

Islet β-cell

Impaired Insulin Secretion

Neurotransmitter Dysfunction

Decreased Glucose Uptake

Islet α-cell

Increased Glucagon Secretion

Increased Lipolysis

Increased Glucose Reabsorption

Increased HGP

DecreasedIncretin Effect

Defronzo RA. Diabetes. 2009 Apr;58(4):773-95.

Injectable Therapies for T2DM and Obesity

This presentation will: • Explain the pathophysiological aspects of T2DM, and

how defects can be addressed with injectable therapies

• Outline incretin-based injectable therapies for T2DM and obesity management and discuss evidence from clinical trials

• Describe established and newly available insulin therapies for treatment of type 2 diabetes.

• Describe how to intensify insulin regimens to achieve glycemic targets

Abnormal Insulin and Glucagon Responses Contribute to Hyperglycemia in Type 2 Diabetes

Healthy (n = 11)Type 2 Diabetes (n = 12)

Mean ± SEData from Müller WA, et al. N Engl J Med. 1970;283:109-115

140

360

300

240Glucose (mg/dL)

0

120

60Insulin (mcU/mL)

100

120

140Glucagon (pg/mL)

80

-60 120 180 240

Time (min)

600

Meal

The Incretin Effect

Time, min

IR In

sulin

, m

U/L

nmol/L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 1200

Control Subjects (n=8)

Type 2 Diabetes(n=14)

Time, min

IR In

sulin

, m

U/L

nmol / L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 120 0

Incretin Effect

Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.

GLP-1 Modulates Numerous Functions in Humans

GLP-1: Secreted upon the ingestion of food

Beta cells: Enhances glucose-dependent

insulin secretion

Brain promotes satiety and reduces appetite

Data from Flint A, et al. J Clin Invest. 1998;101:515-520; Data from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422 Data from Nauck MA, et al. Diabetologia. 1996;39:1546-1553; Data from Drucker DJ. Diabetes. 1998;47:159-169

Stomach: Helps regulate gastric

emptying

Liver: ↓ Glucagon reduces

hepatic glucose output

Alpha cells: ↓ Glucose-dependent

postprandial glucagon secretion

Glucose-Dependent Actions of GLP-1: Effect in Subjects With Type 2 Diabetes

Data are mean ± SE. *P<0.05 Adapted from: Nauck MA, et al. Diabetologia. 1993;36:741-744.

350

300

250

200

150

100

50

0

Insulin (pmol/L)

* ** * *

* * *

GLP-1/PBO infusion

Time (min)

-30 0 60 120 180 240

25

20

15

10

5

0

Glucagon (pmol/L)

Time (min)

-30 0 60 120 180 240

*** *

GLP-1/PBO infusion

GLP-1

17.5

15.0

12.5

10.0

7.5

5.0

2.5

0

*

Glucose (mmol/L)

GLP-1/PBO infusion

***

** *

-30 0 60 120 180 240

Time (min)

Placebo

Strategies for Enhancing GLP-1 Action

• GLP-1 receptor agonists (injectable therapies) – Exenatide – Liraglutide – Albiglutide – Dulaglutide

• DPP-4 inhibitors (oral therapies) – Inhibit actions of DPP-4 – Sitagliptin, Saxagliptin, Linagliptin, Alogliptin

Characteristics of GLP-1 AgonistsExenatide, Liraglutide, Albiglutide, Dulaglutide

Mechanism Mimic prolonged action of GLP-1

EfficacyDecrease A1C levels 0.5%–2.0% (depends on entry of glucose into bloodstream from gut)

Dosing Once- or twice-daily injection, weekly *

Side effects Nausea, vomiting, weight loss

Main riskC-cell thyroid tumors**, long-term safety unknown

Associated with Pancreatitis possible

Nathan DM, et al. Diabetes Care. 2008;31:173-175; Drucker DJ, et al. Lancet. 2006;368:1696- 1705. Exenatide [package insert]. San Diego, CA; Amylin Pharmaceuticals; 2010.; Tanzeum (albiglutide) [prescribing information].

*Dosing depends on GLP-1 agonist **With liraglutide, in rodents only

A1C = glycated hemoglobin; GLP-1 = glucagon-like peptide-1

Marketed GLP-1 RAsCharacteristic Exenatide BID Liraglutide Exenatide ER Albiglutide Dulaglutide

Initial US approval 2005 2010 2012 2014 2014

Trade name Byetta Victoza Bydureon Tanzeum (U.S.) Eperzan (Europe)

Trulicity

Description

Synthetic exendin-4, a peptide identified in H. suspectum that activates the GLP-1 R and is resistant to DPP-4 degradation

GLP-1 modifieda to be resistant to DPP-4 degradation

Exenatide contained in a hydrolyzable polymer microspheres for extended release

An albumin fusion protein made of 2 copies of modified human GLP-1

A fusion protein with 2 disulfide-linked human GLP-1 analog sequence chains, connected by a small peptide linker to human immunoglobulin G4 (IgG4)

Administration Subcutaneous injection

Half-life 2.4 hours 13 hours > 1 week 5 days 5 days

Dosing 2 × daily, before meals

1 × daily, any time 1 × weekly 1 × weekly 1 × weekly

a Amino acid substitution and addition of acyl chain.

Byetta (exenatide) [prescribing information]; Victoza (liraglutide) [prescribing information]; Bydureon (exenatide extended-release for injectable suspension) [prescribing information].; Neumiller JJ. J Am Pharm Assoc. 2009;49(suppl 1):S16-S29.; DeYoung M, et al. Diabetes Technol Ther. 2011;13:1145-1154.; Tanzeum (albiglutide) [prescribing information]; Trulicity (dulaglutide) [prescribing information]; Kuritzky L, et al. PostGrad Med. 2014;126(6):60-72.

Liraglutide

• Liraglutide: 0.6 mg sc QD x 1 week then 1.2 mg sc QD increase to 1.8 mg sc QD if needed • Supplied in a pen • Use: 2-3 pens per month

*P<0.0001 vs monotherapy. **P<0.0001 vs dual therapy. ***P=0.0015 vs glargine. †All liraglutide dosages shown are 1.8 mg QD.

1. Garber A, et al. Lancet. 2009;373:473-481. 2. Nauck M, et al. Diabetes Care. 2009;32:84-90. 3. Pratley RE, et al. Lancet. 2010;375:1447-1456. 4. Marre M, et al. Diabet Med. 2009;26:268-278. 5. Zinman B, et al. Diabetes Care. 2009;32:1224-1230. 6. Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055.

Glucose Control With Liraglutide With/Without Oral Agents

Δ A

1C (%

)

-1.6

-1.2

-0.8

-0.4

0

0.4

-1.33-1.50

-1.13

-1.50

-1.00-1.14 -1.09

-0.5-0.44

-0.9-0.98

-0.51

-0.24

0.230.09

Monotherapy vs Glimepiride 52 Weeks1

Add-on to Metformin 26 Weeks2

Add-on to Metformin 26 Weeks3

Add-on to Sulfonylurea 26 Weeks4

Add-on to Met + TZD 26 Weeks5

Add-on to Met + SU

26 Weeks6

N 746 1091 665 1041 821 581

Treatment Glim

Lir Met Glim +

Met

Lira +Met

Sit + Met

Lira +Met

SU Rosi +

SU

Lira +

SU

Rosi +

Met

Lira +

Rosi + Met

Met +SU

Glar + Met +

SU

Lira +

Met + SU

Baseline A1C (%)

8.4 8.3 8.4 8.4 8.4 8.5 8.4 8.4 8.4 8.5 8.4 8.6 8.3 8.2 8.3

*

****

***

******

*P<0.0001 vs glargine, rosiglitazone, sitagliptin, or SU. **P<0.01 vs metformin. ***P<0.05 vs SU. †All liraglutide dosages shown are 1.8 mg QD.

1. Garber A, et al. Lancet. 2009;373:473-481. 2. Nauck M, et al. Diabetes Care. 2009;32:84-90. 3. Pratley RE, et al. Lancet. 2010;375:1447-1456. 4. Marre M, et al. Diabet Med. 2009;26:268-278. 5. Zinman B, et al. Diabetes Care. 2009;32:1224-1230. 6. Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055.

-4

-3

-2

-1

0

1

2

3

-1.80-2.00

-0.20

-3.38-2.80-2.50

1.60

0.60

2.10

-0.96

1.001.10

-0.42-0.10

-1.50Δ W

eigh

t (kg

) Weight Reduction With Liraglutide: Mono

and Dual Combination Therapy

* ** **

*

*

***

Monotherapy vs Glimepiride 52 Weeks1

Add-on to Metformin 26 Weeks2

Add-on to Metformin 26 Weeks3

Add-on to Sulfonylurea 26 Weeks4

Add-on to Met + TZD 26 Weeks5

Add-on to Met + SU

26 Weeks6

N 746 1091 665 1041 821 581

Treatment Glim

Lir Met Glim +

Met

Lira +Met

Sit + Met

Lira +Met

SU Rosi +

SU

Lira +

SU

Rosi +

Met

Lira +

Rosi + Met

Met +SU

Glar + Met +

SU

Lira +

Met + SU

*

*P<0.01 vs active comparator. †All liraglutide dosages shown are 1.8 mg QD.

1. Garber A, et al. Lancet. 2009;373:473-481. 2. Nauck M, et al. Diabetes Care. 2009;32:84-90. 3. Pratley RE, et al. Lancet. 2010;375:1447-1456. 4. Marre M, et al. Diabet Med. 2009;26:268-278.

Hypoglycemia With Liraglutide: Mono and Dual Combination Therapy

0

8

15

23

30

85

3

8

45

17

33

24

Monotherapy 52 Weeks1

Add-on to Metformin 26 Weeks2

Add-on to Metformin 26 Weeks3

Add-on to Sulfonylurea 26 Weeks4

N 746 1091 665 1041

Treatment† Glim Lira Met Glim + Met

Lira +Met

Sit + Met

Lira +Met

SU Rosi +SU

Lira +SU

*

Pat

ient

s R

epor

ting

Hyp

ogly

cem

ia (%

)

**

Blood Pressure Changes With Liraglutide

-6

-4.5

-3

-1.5

0

1.5

-4.0

-5.6

-2.8

-0.7

-2.3

-3.6

0.5

-1.1-0.9-0.9

0.4

-0.7

-2.3-1.8

Δ S

ysto

lic B

P (m

mH

g)

**

**

Monotherapy vs Glimepiride 52 Weeks1

Add-on to Metformin 26 Weeks2

Add-on to Metformin 26 Weeks3

Add-on to Sulfonylurea 26 Weeks4,5

Add-on to Met + TZD 26 Weeks6

Add-on to Met + SU

26 Weeks7

N 746 1091 665 1041 821 581

Treatment Glim

Lir Met Glim +

Met

Lira +Met

Sit + Met

Lira +Met

SU Rosi +

SU

Lira +

SU

Rosi +

Met

Lira +

Rosi + Met

Met +SU

Glar + Met +

SU

Lira +

Met + SU

*P<0.05 vs comparator. †All liraglutide dosages shown are 1.8 mg QD.

1. Garber A, et al. Lancet. 2009;373:473-481. 2. Nauck M, et al. Diabetes Care. 2009;32:84-90.; 3. Pratley RE, et al. Lancet. 2010;375:1447-1456. 4. Marre M, et al. Diabet Med. 2009;26:268-278.5. Colagiuri S, et al. Diabetes. 2008;57(suppl 2): Abstr. 554-P. 6. Zinman B, et al. Diabetes Care. 2009;32:1224-1230. 7. Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055

Liraglutide: Adverse Events

Adverse Events*

Patients (%)

Monotherapy + Met + Glim + Met + TZD

Lir (n=497)

Glim (n=248)

Lir (n=724)

PBO (n=121)

Lir (n=695)

PBO (n=114)

Lir (n=355)

PBO (n=175)

Nausea 28.4 8.5 15.2 4.1 7.5 1.8 34.6 8.6

Diarrhea 17.1 8.9 10.9 4.1 7.2 1.8 14.1 6.3

Vomiting 10.9 3.6 6.5 0.8 12.4 2.9

Constipation 9.9 4.8 5.3 0.9 5.1 1.1

Headache 9.1 9.3 9.0 6.6 8.2 4.6

Dyspepsia 5.2 0.9

*Adverse events of interest occurring in ≥5% of patients receiving liraglutide.

Victoza (liraglutide) injection prescribing information. Princeton, NJ: Novo Nordisk Inc. 2012.

Nausea Declined Over Time with Liraglutide Monotherapy

Patients (%)

0

3.5

7

10.5

14

Time (weeks)

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Liraglutide 1.2 mg (n=251)Liraglutide 1.8 mg (n=246)Glimepiride 8 mg (n=248)

Liraglutide Monotherapy vs SU

Liraglutide [package insert]. Princeton, NJ: Novo Nordisk Inc. 2010; Garber A et al. Lancet. 2009;373:473-481.

Liraglutide 3mg• Approved December 2014 for treatment of

overweight/obesity • Indications: adults with BMI ≥ 30 or BMI ≥ 27 with

one CV risk factor: hypertension, type 2 diabetes, hypercholesterolemia

• Approved with REMS: follow up and registry for MTC, breast cancer, CV safety

• Supplied as 3 mL pen, 6mg/mL (5 pens/mo.) • Dose titration: 0.6mg daily sc x 7 d; 1.2mg daily x

7 d; 1.6mg daily x 7 d; 1.8mg daily x 7 d; 2.4mg daily x 7 d; 3mg daily maintenance

Liraglutide 3mg QD• Phase 3 - 56-week trials: • Proportion of patients achieving weight loss:

≥ 5% ≥ 10%

Liraglutide 3mg 60.3 31.2

Placebo 24.4 8.7

*Metformin, sulfonylurea, thiazolidinedione, or combination of any 2 of these agents. †Metformin, sulfonylurea, metformin + sulfonylurea, or metformin + pioglitazone.

1. Drucker DJ, et al. Lancet. 2008;372:1240-1250. 2. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258.3. Bergenstal RM, et al. Lancet. 2010;376:431-439. 4. Diamant M, et al. Lancet. 2010;375:2234-2243.5. Buse JB, et al. Lancet. 2013;381:117-124.

Glucose Control With Exenatide ER

Δ A

1C (%

)

-1.9

-1.425

-0.95

-0.475

0

-1.5-1.53

-1.28-1.50

-1.20

-1.48

-1.90

-1.5-1.3

-0.9

-1.6-1.5

-1.15

Add-on to OAs*

30 Weeks1

Monotherapy vs OAs

26 Weeks2

Add-on to Metformin 26 Weeks3

Add-on to Met +/- SU 26 Weeks4

Add-on to OAs†

26 Weeks5

N 258 820 514 456 911

Treatment Exe BID

Exe ER

Sit Pio Met Exe ER

Sit Pio Exe ER

Glar + OAs

Exe ER + OAs

Lira + OAs

Exe ER + OAs

Baseline A1C (%)

8.3 8.3 8.5 8.5 8.6 8.5 8.5 8.5 8.6 8.3 8.3 8.4 8.5

P<0.001 P<0.0001P<0.01P=0.017 P=0.02

Exenatide ER• 2 mg sc every 7 days, w/ or w/o meals • 23G x 5/16” needle • Microsphere release; steady state: 6-7 wks • Not recom. as 1st line Rx or use w/insulin • Add on to metformin, SU, TZD, or combination • Less nausea vs exenatide BID • ↑ weight loss vs exenatide BID: 5.1 lb vs 3.1 lb

@24 wks

*Metformin, sulfonylurea, thiazolidinedione, or combination of any 2 of these agents. †Metformin, sulfonylurea, metformin + sulfonylurea, or metformin + pioglitazone.

1. Drucker DJ, et al. Lancet. 2008;372:1240-1250. 2. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258. 3. Bergenstal RM, et al. Lancet. 2010;376:431-439. 4. Diamant M, et al. Lancet. 2010;375:2234-2243. 5. Buse JB, et al. Lancet. 2013;381:117-124.

-4

-3

-2

-1

0

1

2

3

-2.3-2.0-2.7-2.6

2.8

-2.0

-3.7 -3.6

1.4

-0.8

1.5

-3.6

-0.8

Add-on to OAs*

30 Weeks1

Monotherapy vs OAs

26 Weeks2

Add-on to Metformin 26 Weeks3

Add-on to Met +/- SU 26 Weeks4

Add-on to OAs†

26 Weeks5

N 258 820 514 456 911

Treatment (mg/day)

Exe BID

Exe ER

Sit Pio Met Exe ER

Sit Pio Exe ER

Glar +

OAs

Exe ER + OAs

Lira +

OAs

Exe ER + OAs

P<0.0001

Δ W

eigh

t (kg

)

Weight Reduction With Exenatide ER

P<0.001P<0.001

*Metformin, sulfonylurea, thiazolidinedione, or combination of any 2 of these agents. †Metformin, sulfonylurea, metformin + sulfonylurea, or metformin + pioglitazone.

1. Drucker DJ, et al. Lancet. 2008;372:1240-1250. 2. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258. 3. Bergenstal RM, et al. Lancet. 2010;376:431-439. 4. Diamant M, et al. Lancet. 2010;375:2234-2243. 5. Buse JB, et al. Lancet. 2013;381:117-124.

0

10

20

30

40

1.05.2

11.013.0

1.04.15.4

8.9

31.0

3.03.76.1

3.1

Add-on to OAs*

30 Weeks1

Monotherapy vs OAs

26 Weeks2

Add-on to Metformin 26 Weeks3

Add-on to Met +/- SU 26 Weeks4

Add-on to OAs†

26 Weeks5

N 258 820 514 456 911

Treatment Exe BID

Exe ER

Sit Pio Met Exe ER

Sit Pio Exe ER

Glar +

OAs

Exe ER + OAs

Lira +

OAs

Exe ER + OAs

Pat

ient

s re

porti

ng

hypo

glyc

emia

(%)

Hypoglycemia With Exenatide ER

Exenatide Extended Release: Adverse Events

Adverse Events*

Patients (%)

Monotherapy + Met + Met +/- SU

Exe ER (n=248)

Sit (n=163)

Pio (n=163)

Met (n=246)

Exe ER (n=160)

Sit (n=166)

Pio (n=165)

Exe ER (n=233)

Glar (n=233)

Nausea 11.3 3.7 4.3 6.9 24.4 9.6 4.8 12.9 1.3

Diarrhea 10.9 5.5 3.7 12.6 20.0 9.6 7.3 9.4 4.0

Injection site reaction 10.5 6.7 3.7 10.2 5.0 4.8 1.2 6.0 0

Constipation 8.5 2.5 1.8 3.3 6.3 3.6 1.2

Headache 8.1 9.2 8.0 12.2 9.4 9.0 5.5 9.9 7.6

Dyspepsia 7.3 1.8 4.9 3.3 5.0 3.6 2.4

Vomiting 11.3 2.4 3.0

Fatigue 5.6 0.6 3.0

*Adverse events of interest occurring in ≥5% of patients receiving exenatide extended release.

More Weekly GLP-1 Receptor Agonists

• Albiglutide (modified GLP-1 fused to albumin) • Dulaglutide (GLP-1 analog fused to IgG4) • Resistant to DPP-4 degradation • Similar efficacy as exenatide ER • A1c reduction 0.8 – 1.0% • Studied with metformin, SU, pioglitazone, basal

insulin • Not recommended as first-line therapy

Albiglutide

• 30 mg sc Qwk • Increase to 50 mg sc Qwk if needed • Supplied as single-dose prefilled pen

Dulaglutide

• 0.75 mg sc Qwk • Increase to 1.5 mg sc Qwk if needed • Supplied as single-dose prefilled pen

Safety: Medullary Thyroid Cancer Risk

• All GLP-1 RAs are contraindicated in patients with a personal or family history of MTC or MEN2 because of the occurrence of C-cell tumors in rodents.

• The C-cell tumor risk humans is unknown, because human relevance could not be determined in clinical trials.

• The value of routine calcitonin and/or ultrasound monitoring is uncertain.

Victoza® PI 2013.; Bydureon® PI 2013. Parks M, et al. N Eng J Med. 2010;362:774-777.

Safety: Renal Impairment

• Exenatide BID or ER is not recommended in those with severe renal impairment or end-stage renal disease (CrCl<30 mL/min) and all GLP-1 RAs should be used with caution in patients with renal transplantation or moderate renal impairment.

Johansen O, et al. Br J Clin Parmacol. 2008;66:568-569.;Weise WJ, et al. Diabetes Care. 2009;32:e22-e23. Ferrer-Garcia JC, et al. Diabetes Med. 2010;27:728-729. López-Ruiz A, et al. Pharm World Sci. 2010;32:559-561.

Safety: Pancreatitis

• Pancreatitis has been reported with all incretin-based therapies, although no causal relationship has been established.

• Patients should know signs and symptoms of pancreatitis and stop taking incretin-based therapies if signs and symptoms occur.

• If pancreatitis is confirmed, therapy should not be restarted.

Ahmad SR, et al. N Engl J Med. 2008;358:1970-1971.; Garg R, et al. Diabetes Care. 2010;33:2349-2354.; Byetta® PI 2013.; Victoza® PI 2013.; Bydureon® PI 2013.; Januvia® PI 2013.; Onglyza® PI 2013.; Tradjenta® PI 2013.; Nesina® PI 2013.

CV OUTCOME TRIALS with GLP-1RAs

ELIXA – Lixisenatide (not yet approved in the USA) No CV risk or benefit – Neutral effect No increase in CHF

Trials ongoing with the other drugs in the class

Synthetic Human Amylin AnalogPramlintide

Pramlintide [package insert]. San Diego, CA; Amylin Pharmaceuticals, Inc; 2008.

MechanismAmylin mimetic: !PPG, suppresses glucagon secretion, slows gastric emptying, promotes satiety

Efficacy Modest ( ! A1C 0.5%)

Advantages No dosage adjustment required in renal impairment

Disadvantages

Nausea, headaches, anorexia, vomiting, abdominal pain, fatigue, dizziness, risk of severe hypoglycemia with insulin Only approved in combination with prandial insulin but cannot be combined in the same syringe

ContraindicationsConfirmed diagnosis of gastroparesis, hypoglycemia unawareness

When To Start Insulin in T2DM

• When combination oral/injectable agents become inadequate

• Unacceptable side effects of oral/injectable agents

• Patient wants more flexibility • Special circumstances (i.e. steroid use,

infection, pregnancy) • Patients with hepatic or renal disease, • Patients with CAD, ↑TG

CAD=coronary artery disease; T2DM=type 2 diabetes mellitus; TG=triglycerides.

Holman et al. NEJM. 2009; 361:1736-1747; Lebovitz HE. Diabetes Rev. 1999;7(3):139-153

Key Points: Insulin Initiation• Diabetes is a progressive disease and many individuals with T2DM eventually need insulin to control their blood glucose

• There are cultural taboos and misconceptions regarding insulin therapy; it is important to understand and acknowledge patients' specific concerns and design individualized treatment plans that fit their needs

• Start with a simple regimen, such as a once-daily basal insulin analog, and up-titrate the dose based on FPG; if A1C remains high when FPG is in the target range, add a DPP-4 inhibitor, a GLP-1 RA, or mealtime insulin

T2DM=type 2 diabetes mellitus; FPG=fasting plasma glucose; DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; RA=receptor agonist; A1C=glycated hemoglobin.

1. Garber AJ, et al. Endocr Pract. 2013;19:327-336. 2. Peragallo V. Diabetes Educ. 2007;33:60S–65S.

Key Points: Insulin Initiation• Allow patients to give the first injection during the

office visit (because the first injection is often the biggest hurdle)

• Alternately, to help diminish fear, give patient a mock shot as soon as insulin is discussed (this can be done before insulin is initiated) 

• Insulin pens facilitate the initiation and acceptance of insulin

• PCP and/or nurse educator should provide ongoing, enthusiastic support, advice, and trouble-shooting

PCP=primary care provider.

Insulin Pens • More convenient than

traditional vial and syringe • More accurate, repeated

doses • Easier to use for those with

visual or fine motor skill impairment

• Less injection pain – Polished and coated needles are

not dulled by insertion into a vial of insulin before a second insertion into the skin

Gebel E, ADA. 2012 Insulin Pens. Jan. 2012 Available at, http://forecast.diabetes.org/magazine/features/2012-insulin-pens, accessed Oct. 5, 2013.

Insulin Therapy in Type 2 Diabetes Current Strategies

• Basal insulin therapy – Long-acting insulin analog once daily – Intermediate-acting NPH at bedtime

• Human or analog insulin (prandial or premixed w/ intermediate) - Once daily at largest meal - Twice daily (breakfast and dinner) - Three times daily (with each meal)

• Intensive insulin therapy - Basal + - rapid-acting analog insulin

- Once daily at largest meal - Twice daily at meals - Three times daily (with each meal)

• Insulin pump therapy

Holman R. New Engl J of Med. 2007 Oct 25;357(17):1716-30.

NPH=Neutral Protamine Hagedorn.

Insulin Analogs More Closely Match the Physiologic Insulin Profile Than Human Insulin

• Bolus (meal-related) insulin analogs – Rapid absorption – Peak action coincides with peak carbohydrate

absorption • Basal insulin analogs

– Slow and steady rate of absorption – Protracted action

Nathan DM, et al. Diabetes Care. 2006;29:1963-1972

Long-Acting Insulin Analogs vs NPH In Type 2 Diabetes

A Meta-Analysis

• Long-acting analogs provide comparable glycemic control to NPH

• Reduced risks of nocturnal and symptomatic hypoglycemia

• May be associated with less weight gain than NPH

1. Riddle MC, et al. Diabetes Care. 2003;26:3080-3086.

NPH=Neutral Protamine Hagedorn.

Pitfalls and Caveats In the Use of Basal Insulin (BI)

PP=postprandial; BI=basal insulin; OHA=oral hypoglycemic agents; SU=sulfonylurea.

The Challenge The Solution

Uptitrating dose based on elevated pre-supper blood glucose → nocturnal hypoglycemia

• Post-lunch hyperglycemia is the culprit; only titrate BI based upon fasting blood glucose

Over-reliance on BI to control PP hyperglycemia when added to non-prandial agents (eg, metformin, thiazolidinediones)

• As both fasting and PP hyperglycemia are present, consider use of a prandial agent before/at time of BI addition

Delay in down-titration of BI with improved glycemia → hypoglycemia and pre-emptive eating

• Discuss this scenario with patient as glycemic control is re-established: “Less insulin is needed to maintain control than establish control”

• Reduction of OHAs, such as SUs or glinides, may also be required

At Some Point, Raising Basal Dose Alone Will Be Inadequate, Failing to Address PPG

Time4:00 16:00 20:00 24:00 4:00

Breakfast

Lunch Dinner

8:0012:008:00

Plasma Insulin

(µU/mL)

75

50

25

0

Mealtime insulin response is missing; high postprandial readings every meal

Basal insulin

This may lead to hypoglycemia if food changes or meals are missed

Adapted from: Unger, J. Initiating insulin therapy in patients with type 2 diabetes. Diabetes Management in Primary Care. Lippincott. 2008.

PPG = post prandial glucose; µU=micro units; mL=milliliter.

Incretin-Based Therapy in Combination With Basal Insulin A Promising Tactic for the Treatment of Patients With T2DM

• Consider non-insulin options with synergistic mechanisms of action and low hypoglycemia risk when intensifying regimens beyond basal insulin • DPP-4 inhibitors when A1C reductions of <1.0% are

needed • GLP-1 receptor agonists when A1C reductions ≥1.0%

are needed (and patients may benefit from possible weight loss)

• Insulin doses may be able to be – or may need to be – lowered

• Targets insulin deficiency and glucagon excess

42

DPP-4=dipeptidyl peptidase-4 ;GLP-1=glucagon-like peptide-1; A1C=glycated hemoglobin; T2DM=type 2 diabetes mellitus.

Vora J, et al. Diabetes Metab. 2013 Feb;39(1):6-15.

Mea

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-7

-4.75

-2.5

-0.25

2

ΔTDD (U/day) ΔA1C (%) ΔWt (kg) ΔHypo (EPY)

0.2

Adding a GLP-1 RA to Basal Insulin Therapy with or Without OADs in T2DM Improves Glycemic Control

a Hypo, BG < 54 mg/dL; major hypo, loss of consciousness or seizure or assistance required. b P < .05; c P < .001.

Mean duration of diabetes: 12 years.

1. Buse JB, et al. Ann Intern Med. 2011;154:103-112.

GLAR + EXE ± MET ± PIO vs GLAR + PBO ± MET ± PIO (30 weeks)

• Patients receiving EXE had 8%-33% more GI adverse events and headaches than patients receiving PBO

• 1 patient in the PBO group had 2 majora hypoglycemic episodes

N = 259

DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; EXE=exenatide; PIO=pioglitazone; GLAR=glargine; PBO=placebo; MET=metformin; EPY=Events per-participant/per-year; Hypo=hypoglycemia; TDD=total daily dose; U=unit; kg=killigram; INS=insulin; A1C=glycated hemoglobin; Wt=weight; T2DM=type 2 diabetes mellitus; BG=blood glucose; mg=milligrams; dL=deciliters.

Options When Not at Goal with 1 Injection of Basal Insulin

• Basal Plus Add prandial insulin at main meal or • Switch to Premixed Insulin (if regular meal schedule)

or • Switch to Basal/Bolus or • Add an incretin-based therapy (DPP-4 inhibitor or

GLP-1 RA, if patient is not already on incretin therapy)

1. American Association of Clinical Endocrinologists. Endocrine Practice. 2011;17(S2):1-53. 2. Garber AJ, et al. Endocr Pract. 2013;19:327-336.

DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; RA=receptor agonist

Meal-Time Insulin Rapid-Acting Analogs (Aspart, Glulisine, Lispro) vs Regular

Hours

Howey DC, et al. Diabetes. 1994;43:396–402.

10

8

6

4

2

00 1 2 3 4 5 6 7 8 9 10 1112

Insulin Activity

Regular Human Insulin

Timing of food

absorbed

Analog insulin

The Basal-Bolus Insulin Concept• Basal insulin

– Controls 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 postmeal – 10% to 20% of total daily insulin requirement at each

meal • For ideal insulin replacement therapy, each component

should come from a different insulin with a specific profile

1. Riddle MC, et al. Diabetes Care. 2003;26:3080-3086; 2. Leahy JL et al. Insulin Therapy. Marcel Dekker, Inc. Burlington, VT: 2002.

0600 0800 18001200 2400 0600Time of day

20

40

60

80

100 B L D

Basal-Bolus Insulin Treatment with Insulin Analogs

µU=milli units; mL=milliliters; B=breakfast; L=lunch; D=dinner.

Glargine, Detemir or Degludec

Lispro, glulisine, or aspart

Normal pattern

Insulin (µU/mL)

1. Leahy JL et al. Insulin Therapy. Marcelle Dekker, Inc. Burlington, VT: 2002.

Effect of Adding 1, 2, or 3 Pre-meal Rapid-acting Insulin Injections To a Background of Basal Insulin Analog

Therapy in Patients Requiring Therapy Intensification

0

13

25

38

50

1 Injection 2 Injections 3 Injections

A1C <7.0%Hypo (%)

Davidson MB, et al. Endocr Pract. 2011;17:395-403.49

Pati

ents

(%

) Ach

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ng

A1C

<7.

0% a

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24

A1C=glycated hemoglobin.

Inhaled Human Insulin• Approved July 2014 • Dry powder, human regular insulin • Adsorbed onto Technosphere microparticles • Dissolves immediately when inhaled • Ultra-rapid acting: peak concentration at

12-15 minutes, back to baseline at 180 minutes

• Bioavailability: 21-30% of subcut. dose • Mealtime glycemic control • Need to use with basal insulin in type 1 DM

Inhaled Human Insulin• Adverse Effects/Contraindications

– Hypoglycemia: similar or lower than sc insulin – Decreased FEV1: small, occurs w/i first 3 months,

potentially reversible with discontinuation – Lung cancer: 2 cases in clinical trials-both heavy

smokers – Not recommended in smokers or recent stoppers – Contraindicated in COPD, asthma – REMS: baseline, 6 mo. and annual spirometry -5 year monitoring to assess risk of lung cancer, change in PFTs

4:00 16:00 20:00 24:00 4:00

Breakfast Lunch Dinner

8:0012:008:00Time

Plasma Insulin

Biphasic Analog Insulin (Premixed Insulin)

1. Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York, NY: Marcel Dekker; 2002:87. 2. Nathan DM. N Engl J Med. 2002;347(17):1342–1349.

Concentrated InsulinsApproved Conc Volume Supplied #units Admin. Features

Glargine U-300

February 2015 3X 1/3 Prefilled Pen

450 QD More compact sc depot with smaller surface area; “Flatter” insulin

Lispro U-200

May 2015 2X 1/2 Prefilled Pen

600 AC TID Bioequiv. to Lispro U-100; Similar time to max. conc.

Regular U-500

1952 (Beef) 1997 (Human)

5X 1/5 Vial (20 mL) 10,000 AC BID-TID

Prefilled pen approved Jan2016

Hypoglycemia: Clinical Consequences

Acute

• Symptoms (sweating, irritability, confusion)

• Accidents • Falls

Long-term• Recurrent hypoglycemia

and hypoglycemia unawareness

• Refractory diabetes • Dementia (elderly) • Cardiovascular events

– Cardiac autonomic neuropathy

– Cardiac ischemia – Fatal arrhythmia – Angina

1. Cryer PE, et al. Diabetes Care. 2003;26:1902-1912.; 2. ADA. Diabetes Care. 2013;36(suppl 1):S11-S66; 3. Zammit NN, et al. Diabetes Care. 2005;28:2948-2961.

Real-World Choices Depend On the Patient

• Injection frequency preference − Some patients may prefer premix

• Frequency of self-monitoring of blood glucose • Variability of lifestyle, including meal timing and

carbohydrate content of meals • Presence of postprandial hyperglycemia • Patient’s ability to follow the prescribed regimen • Educational and emotional support available to patient • Cost of analogue insulin options may be nearly double

that of NPH or regular insulin

Monami M. Diabetes Obes Metab. 2009;11(4):372-8.

Summary• Many patients on basal insulin therapy will

ultimately require treatment intensification • Current options include:

– Addition of mealtime control via addition of prandial insulin, leading to multiple daily insulin therapy

– Switch to premix insulin – Add a SGLT-2 inhibitor, DPP-4 inhibitor or a

GLP-1 agonist

DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1.

Garber AJ, et al. Endocr Pract. 2013;19:327-336.

Thank you!