The Role of the Pharmacist in Ensuring Their Safe and

Effective Use in Patients

Basal Insulin Therapy in the

Treatment of Insulin Resistant

Type 2 Diabetes:

Joshua J. Neumiller, PharmD, CDE, FASCP

Washington State University

Objectives

1. Describe the reasons for the use of high concentration insulin

formulations in the treatment of type 2 diabetes

2. Discuss the clinical, pharmacokinetic and pharmacodynamic

profiles for current and emerging basal insulins

3. Implement strategies for safely converting between U-100

and concentrated insulin formulations using different syringes

and pen devices in patients with type 2 diabetes

4. Review currently available insulin pens and syringes used for

the administration of insulin

5. Explain and apply strategies to overcome the barriers to

insulin-mediated glucose control

Disclosures

Joshua J. Neumiller, PharmD, CDE, FASCP has

received research grant support from Johnson &

Johnson, AstraZeneca, Merck and Novo Nordisk.

He has served on a speaker bureau for Novo

Nordisk and Janssen, and has served on an

advisory board for Sanofi and Janssen.

The Diabetes Epidemic

http://www.cdc.gov/media/pressrel/2010/r101022.html. Accessed February 5, 2015. CDC. National Diabetes Statistics Report, 2014. http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf. Accessed April 15, 2015.

Diabetes in the United States

29.1 million people (9.3% of the population) have diabetes

8.1 million are undiagnosed

CDC estimates that 1 in 3 adult Americans will have diabetes

by 2050

Type 2 Diabetes (T2DM)

Associated with obesity, older age, decreased physical activity,

and race/ethnicity

Incidence in children and adolescents is increasing

Estimated total costs in 2012: $245 billion

Type 2 Diabetes

Characterized by chronic hyperglycemia

Associated with microvascular and

macrovascular complications

Generally arises from a combination

of insulin resistance and -cell dysfunction

Scheen AJ. Acta Clin Belg. 2003;58(6):335-41.

By the time a person is diagnosed with type 2 diabetes, approximately

how much -cell function has been lost?

1.

HOMA = homeostasis model assessment.

Based on data of UKPDS 16. Diabetes. 1995;4(11):1249-1258.

Progressive Deterioration in -Cell Function Over Time

Beta

-Cell

Fu

ncti

on

(%,

HO

MA

)

Insulin Intensive or

in Combination

25

100

75

0

50

-12 -10 -6 -2 0 2 6 10 14

Years from Diagnosis

-8 -4 4 8 12

Combination

Therapy

Monotherapy

Pathophysiologic Defects in Type 2 Diabetes: The Ominous Octet

Decreased Incretin Effect

Neurotransmitter Dysfunction

Islet -cell Impaired

Insulin

Secretion

Decreased

Glucose

Uptake

Islet a-cell Increased

Glucagon

Secretion

Increased Lipolysis

Increased

Glucose

Reabsorption

Increased

HGP

DeFronzo RA. Diabetes. 2009;58(4):773-795.

Hyperglycemia

Insulin Resistance

~90% of People with Type 2 Diabetes

are Overweight or Obese

World Health Organization, 2005. http://www.who.int/dietphysicalactivity/publications/facts/obesity.

Insulin Resistance

Major defect in individuals with type 2 diabetes

Reduced biological response to insulin

Closely associated with obesity

Associated with cardiovascular risk

Type 1 diabetes patients can be insulin resistant

as well

1. American Diabetes Association. Diabetes Care. 1998; 21:310-314. 2. Beck-Nielsen H, Groop LC. J Clin Invest 1994; 94:1714-1721. 3. Bloomgarden ZT. Clin Ther 1998; 20:216-231. 4. Boden G. Diabetes 1997; 46:3-10.

More than 80% of Patients Progressing to Type 2 Diabetes

are Insulin Resistant

Haffner SM, et al. Circulation. 2000;101:975-980.

83% Insulin resistant; low insulin secretion

(54%)

Insulin resistant;

good insulin secretion

(29%)

Insulin sensitive;

good insulin secretion

(1%)

Insulin sensitive;

low insulin secretion

(16%)

Insulin Resistance Reduces Response to Circulating Insulin

Insulin

resistance

Glucose output Glucose uptake Glucose uptake

Hyperglycemia

Liver Muscle Adipose

tissue

Insulin/medication

requirements needed

to maintain

glycemic control

IR

Treatment Options for Type 2 Diabetes

12 Pharmacotherapy Options Insulin

Bolus insulin

Insulin lispro (Humalog)

Insulin aspart (NovoLog)

Insulin glulisine (Apidra)

Insulin human inhaled (Afrezza)

Regular human insulin

(Humulin R)

(Novolin R)

Basal insulin

Insulin NPH

(Humulin N)

(Novolin N)

Insulin detemir (Levemir)

Insulin glargine U-100 (Lantus)

Insulin glargine U-300 (Toujeo)

Oral Medications

a-glucosidase inhibitors (AGI)

Biguanides

Bile acid sequestrants (BAS)

Dipeptidyl peptidase-4 (DPP-4)

inhibitors (gliptins)

Dopamine agonists

Glitinides

Sulfonylureas

Sodium glucose co-transporter-2

inhibitors

Thiazolidinediones (TZDs or glitazones)

Non-insulin injectable agents

Glucagon-like peptide-1 (GLP-1)

agonists

Amylinomimetics

Cornell S, et al. Postgrad Med. 2012;124(4):84-94. http://www.pdr.net/search-results?q=afrezza. Accessed January 30, 2015. http://www.pdr.net/full-prescribing-information/toujeo?druglabelid=3688. Accessed March 26, 2015.

Glucose-Lowering Comparison

FPG = fasting plasma glucose; PPG = postprandial glucose.

Unger J, et al. Postgrad Med. 2010;122(3):145-157. Cornell S, et al. Postgrad Med. 2012;124(4):84-94.

Monotherapy Route of

Administration

Targets Insulin

Resistance

Target Glucose:

FPG or PPG

A1C Reduction

(%)

Sulfonylurea Oral No Both 1.52.0

Metformin Oral Yes FPG 1.5

Glitazones Oral Yes Both 1.01.5

Meglitinides Oral No PPG 0.52.0

AGIs Oral No PPG 0.51.0

DDP-4 inhibitors Oral No PPG 0.50.7

Bile acid sequestrant Oral No PPG 0.4

Dopamine agonists Oral No PPG 0.4

SGLT-2 inhibitors Oral glucose toxicity FPG 0.71.1

GLP-1 agonists Injectable No Short-acting PPG

Long-acting Both 0.81.5

Amylin analogs Injectable No PPG 0.6

Insulin Injectable glucose toxicity Basal FPG

Bolus PPG

as much as

needed

Basal Insulin Therapy: Concept and Physiology

UKPDS: Progressive Deterioration in Glycemic Control Over Time

UKPDS Group. Lancet. 1998;352:837-853. Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25.

HbA1C Level

Intensive

Conventional

Time from Randomization (y)

Med

ian

A1

C (

%)

9

8

7

6

0

3 0 9 6 15 12

Currently Available Insulins

Insulin Type Onset Peak, h Duration of Action, h

Rapid-acting analogs

Insulin lispro, aspart,

glulisine

Insulin human inhaled

15 min

1215 min

0.51.5

~1.0

35

2.53.0

Short-acting

Regular human (U-100)

Regular human (U-500)

3060 min

3060 min

24

48

58

1415

Intermediate-acting

Human NPH insulin

13 h

612

1224

Long-acting (basal)

Insulin glargine

Insulin detemir

24 h

13 h

No pronounced

peak

2024

1820

Ultralong-acting (basal)

Insulin glargine U-300

6 h

No pronounced peak

36

Walia M and Molitch M. JAMA. 2014;311:2315-2325. Accessed March 24, 2014. http://www.pdr.net/full-prescribing-information/toujeo?druglabelid=3688. Accessed March 26, 2015. http://www.pdr.net/full-prescribing-information/afrezza?druglabelid=3540. Accessed April 5, 2015.

Thinking Like a Pancreas

8 AM 6 PM 3 PM 12 NOON 9 PM 3 AM 7 AM

No food Meals

Less overnight

More for waking up

Time

PK Profile of Currently Available Insulins

PK = pharmacokinetic; NPH = neutral protamine Hagedorn.

Adapted from Hirsh IB. NEJM. 2005;352:174-183. Flood TM. J Fam Pract. 2007;56(suppl 1):S1-S12. Becker RH, et al. Diabetes Care. 2014;pii:DC_140006. http://www.pdr.net/full-prescribing-information/afrezza?druglabelid=3540. Accessed April 5, 2015.

0 12 16 20 24 8 4

Pla

sm

a I

nsu

lin

Levels

2 14 18 22 10 6

Intermediate (NPH insulin)

Long (Insulin detemir)

Long (Insulin glargine)

Time (hours) 26 28 30 32 34 36

Ultralong (U300 glargine)

Aspart, Lispro, Glulisine

Regular

Inhaled insulin

Insulin Regimens Used in T2DM

Basal only

1 injection

Added to oral agents

Basal plus

2 injections or 1 injection + 1 inhalation

Adding on