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•Updates in Type 2 Diabetes

• Ernest Asamoah, MD FRCP

1

Objectivess

• Know the current diagnostic criteria for type 2 diabetes and who to screen for diabetes

• Fully understand and discuss the pathophysiology of type 2 diabetes

• Utilize the current management tools that are available

Diabetes: Historical Perspective

Areteus of Cappadocia

writes first accurate

clinical description of

diabetes1

Willis describes sugar taste in

urine; eventually led to the

addition of the term “mellitus”1

Langerhans describes

islet cells of pancreas1

Mering and

Minkowski discovers

role of pancreas in

diabetes1

Banting and

Best discover

insulin1

2nd C AD 1674 1869 1889 1922 1923 1929

Mass production

of bovine insulin2

Hagedorn adds

protamine to insulin

to prolong insulin

effects2

1st blood glucose

meter created5

Mass production

of recombinant

human insulin2

A1C test

created5

Human insulin

receptor sequenced2

Human insulin analogs developed2

1st approved CGMS device (1999)8,9

Pramlintide approved for use (2005)10

DPP-4 inhibitors11 GLP-1 agonists approved for use12

TZDs approved (1999)13

1936 1950s 1969 1978 1979 1983 1985 1987 1995 1996-present

1st commercial

insulin pump6

Metformin

synthesized3

Sulfonylureas

become available4

Metformin approved

for use in the U.S.3

1st licensed

insulin pen7

3

Patients reaching glycemic target

Glycemic Targets Are Not Being Achieved Worldwide

DICE = Diabetes in Canada Evaluation; NHANES = National Health and Nutrition Examination Surveys; RECAP-DM = Real-life

Effectiveness and Care Patterns of Diabetes Management.

1. Harris SB et al. Diabetes Res Clin Pract. 2005;70:90–97.

2. Ong et al. Ann Epidemol. 2008;18:222–229.

3. Guisasola et al. Diabetes Obes Metab. 2008;10:8–15.

UNITED STATES

(NHANES)2 HbA1c <7%

57%

43%

EUROPE

(RECAP-DM)3 HbA1c <6.5%

74%

CANADA

(DICE)1 HbA1c <7%

51%

49%

26%

Patients not reaching glycemic target

4

Diabetic

Retinopathy

Leading cause

of blindness

in adults

Diabetic

Nephropathy

Major cause of

kidney failure

Cardiovascular

Disease

Stroke

Diabetic

Neuropathy

Major cause of lower

extremity amputations

CV Disease & Stroke

account for ~65% of

deaths in T2D patients

Type 2 Diabetes Associated with Serious Complications

CV = cardiovascular.

National Institute of Diabetes and Digestive and Kidney Diseases. National Diabetes Statistics fact sheet: general information and national

estimates on diabetes in the United States, 2005. Bethesda, MD: U.S. Department of Health and Human Services, National Institute of

Health, 2005.

5

Burden of Diabetes USA: Morbidity

• Diabetic Retinopathy – #1 cause of blindness in working age adults

• Diabetic Nephropathy – #1 cause of End Stage Renal Disease – 43% of cases

• Diabetic Amputations – # 1 Cause of Nontraumatic Lower Extremity Amputations

• Diabetic Vascular Disease – 2-6 fold more likely to have heart disease – diabetes a CVD equivalent

6

Economic Consequences of Diabetes

Total Annual Cost in 2002: $132 Billion

Disability and early mortality

$40 billion

Diabetes and diabetes supplies

$23 billion

Chronic complications $25 billion

$44 billion

General medical conditions

Indirect costs* = $40 billion Direct costs† = $92 billion

Stolar MW et al. JMCP. 2008;14:S1–S19.

*Indirect costs include lost productivity, disability, and premature mortality. †Direct costs include: hospital inpatient care, nursing home care, physician office visits, total home healthcare costs, costs associated

with hospice care, and diabetes supplies.

7

Adapted from Kendall D, Bergenstal R. © International Diabetes Center.

Glucose

Relative

Function

0

100

200

300

-10 -5 0 5 10 15 20 25 30

50

150

250

350

Years of diabetes

Insulin resistance

Insulin level

Fasting glucose

Beta-cell failure

Postmeal glucose

At risk for

diabetes

Type 2 Diabetes: Progression

AACE Criteria for Diagnosis of Diabetes1

1. Handelsman Y. Endo Pract. 2011;17(suppl 2):1-53. 2. ADA. Diabetes Care. 2012;35(suppl 1):S11-S63.

a These guidelines provided by AACE mirror values for diabetes diagnosis criteria by ADA. However, the A1C range for prediabetes is 5.7-6.4% in the ADA guidelines.2

AACE, American Association of Clinical Endocrinologists; ADA, American Diabetes Association.

Test Result Diagnosis

Fasting plasma glucose, mg/dL ≤99 Normal

100-125 Impaired fasting glucose

≥126 Diabetes, confirmed by repeating the test on a different day

Postprandial plasma glucose, mg/dL (oral glucose tolerance test, 2 hours after ingestion of 75-g glucose load)

≤139 Normal

140-199 Impaired glucose tolerance

≥200 Diabetes, confirmed by repeating the test on a different day

Hemoglobin A1C, % (as a screening test)

≤5.4 Normal

5.5-6.4a High risk/prediabetes; requires screening by glucose criteria

≥6.5 Diabetes, confirmed by repeating the test on a different day

1. Adapted from Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25. 2. DeFronzo RA. Diabetes. 2009;58(4):773-795.

HOMA, homeostasis model assessment.

Decline of β-Cell Function: Progressive Nature of Diabetes

UKPDS data suggests loss of -cell function precedes diagnosis by many years 1,2

-c

ell

fun

ctio

n

(% o

f n

orm

al b

y H

OM

A)

0

20

40

60

80

100

-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6

Time of diabetes diagnosis

β-cell function is ~50% of normal at time

of T2DM diagnosis

Year

UNDIAGNOSED

A more recent study suggests that over 80% of β-cell function is lost by the time of diagnosis2

Primary Sites of Action for Antidiabetic Pharmacotherapies

Glucose uptake Hepatic glucose

production

Impaired insulin secretion

Insulin deficiency = Carbohydrate metabolism

Insulin resistance

1. Fonseca V. Drug therapy. In: Cefalu WT, Gerich JE, Leroith D, eds. The CADRE Handbook of Diabetes Management. 1st ed. 2004:99-113.

2. Drucker DJ. Cell Metab. 2006;3:153-165.

3. Riddle M, Lutz K, Pencek R, et al. Diabetes Care. 2009;32(9):1577-1582.

4. Rosenstock J, Riddle MC. In: Cefalu WT, Gerich JE, Leroith D, eds. The CADRE Handbook of Diabetes Management. 1st ed. 2004.

Liver1 Muscle/Fat1,4

Intestine1,3 Pancreas1,2

• Glitinides • Sulfonylureas • GLP-1 analogs • DPP-4 inhibitors

• Biguanides • Thiazolidinediones

• Biguanides • Thiazolidinediones • Insulins

• Amylin analog • α-glucosidase inhibitors

ADA/EASD 2009 Consensus Statement for the Management of Type 2 Diabetes

EASD, European Association for the Study of Diabetes.

Adapted from Nathan DM et al. Diabetes Care. 2009;32(1):193-203.

Tier 1: Well-validated core therapies

• Reinforce lifestyle interventions at every visit

• Check A1C every 3 months until A1C is <7%

– Then check A1C at least every 6 months

At diagnosis:

Lifestyle +

Metformin Lifestyle + Metformin +

Sulfonylurea

Lifestyle + Metformin +

Intensive Insulin


Basal Insulin

Step 1 Step 2 Step 3


Pioglitazone +

Sulfonylurea


Pioglitazone


GLP-1 agonist


Basal Insulin

Tier 2: Less well-validated therapies

AACE/ACE Diabetes Algorithm for Glycemic Control A1C goal ≤6.5%*

Adapted from Rodbard H. Endo Pract. 2009;15(6):540-559. Available at www.aace.com/pub.

Lifestyle Modification

A1C 6.5%–7.5%** A1C 7.6%–9.0% A1C >9.0%

MET † TZD2 DPP-41 AGI3

Monotherapy Dual therapy8

2-3 months***

Dual therapy

MET + GLP-1 or DPP-41

TZD2

Glinide or SU4

TZD + GLP-1 or DPP-41

MET + Colesevelam

AGI3

2-3 months***

Triple therapy

2-3 months***

Insulin ± other agent(s)7

2-3 months***

Triple therapy9

MET + GLP-1 or DPP-41

+ TZD2

Glinide or SU4,6

2-3 months***



MET +

GLP-1 or DPP-41

or TZD2

Glinide or SU4,5 Insulin ± other agent(s)6

MET +

GLP-1 or DPP-41 + TZD2

GLP-1 or DPP-41

+ SU7

TZD2

MET +

GLP-1 or DPP-41

+ SU7

TZD2

GLP-1 or DPP-41 + TZD2

Symptoms No symptoms

Drug-naive Under treatment

* May not be appropriate for all patients ** For patients with diabetes and A1C <6.5%, pharmacologic Rx

may be considered *** If A1C goal not achieved safely † Preferred initial agent 1 DPP-4 if ↑ PPG and ↑ FPG or GLP-1 if ↑↑ PPG 2 TZD if metabolic syndrome and/or nonalcoholic fatty liver disease (NAFLD) 3 AGI if ↑ PPG 4 Glinide if ↑ PPG or SU if ↑ FPG 5 Low-dose secretagogue recommended 6 a) Discontinue insulin secretagogue with multidose insulin

b) Can use pramlintide with prandial insulin 7 Decrease secretagogue by 50% when added to GLP-1 or DPP-4 8 If A1C <8.5%, combination Rx with agents that cause hypoglycemia

should be used with caution 9 If A1C >8.5%, in patients on dual therapy, insulin should be considered

GLP-1

Reproduced with permission from AACE.

Are We Waiting Too Long to Make an Impact?

Study Design: A prospective, population-based study using retrospective observational data. All 7208 complete courses of treatment with nondrug therapy, sulfonylurea monotherapy, metformin monotherapy, and combination oral antihyperglycemic therapy between 1994 and 2002 were identified among members of the Kaiser Permanente Northwest Region. Mean cumulative glycemic burden, defined as A1C-months >8.0%, was calculated for each treatment. Intervention was defined as abandonment or change in therapy.

Brown JB. Diabetes Care. 2004;27(7):1535-1540.

Diet + exercise

Sulfonylurea alone

Metformin alone

Metformin + sulfonylurea

25.6 months

20.5 months

8.7 months

14.5 months

Mean months A1C above 8% before treatment intervention

8.6%

9.1%

8.8%

9.6%

0 5 10 15 20 25 30

A1C prior to treatment intervention Current treatment

Delay in changing therapy after failure of oral medications

14

The Multifactorial Pathogenesis of T2DM

Impaired insulin secretion and insulin resistance underlie all other

pathophysiologic defects leading to hyperglycemia

15

Additional TEAM EFFORTS

Diabetes Education: RN, RD, Pharmacist, staff, support groups

Group Visits: (telling their story) patients teaching patients

Self Management Support: Improved Self Care (teach them to “fish” instead of giving them a fish) Care Plan-Action Plan, etc.

16

The BAGAGE of Diabetes (blame, shame, guilt, anger, punishment, deprivation, etc.)

There are better motivators…recommend tie these up in a big black trash bag and throw them away… “Tools not Rules”

17

Incretin Effect *

*

*

*

* *

*

18

The Incretin Effect in Healthy Individuals and in Patients With T2DM

19

Impaired Insulin and Dysfunctional Glucagon Dynamics Lead to Hyperglycemia

in T2DM

20

Normal Glucose Homeostasis: Role of Incretins1,2

α

β Incretin Effect

Decreased

Glucose

Production

Increased

Glucose

Uptake

Liver

Glucose

Homeostasis

Pancreatic cells respond to high levels of incretins

2

In response to meals, incretin hormones (GIP and GLP-1) are increasingly released from the small intestine

Glucagon Secretion

Insulin Secretion

Fat

Incretins (GIP/GLP-1)

Pancreatic alpha cell

Pancreatic beta cell β

α

1

GI Tract Pancreas

DPP-4 enzymes break down incretins

3

DPP-4 Enzymes

Indirect

suppression

of glucagon

GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1; DPP-4=dipeptidyl peptidase-4.

1. Kim W et al. Pharmacol Rev. 2008;60:470-512.


21

Pancreas α

β Diminished

Incretin Effect

Increased

Glucose

Production

Impaired

Glucose

Uptake

Liver

Hyperglycemia

Fat

Insulin Secretion

Glucagon Secretion

β

α

Incretins (GIP/GLP-1)

Pancreatic alpha cell

Pancreatic beta cell

GI Tract

DPP-4 Enzymes

T2DM: Role of Incretins1,2

In adults with T2DM, incretins are released, but the incretin-mediated effects are diminished

1

Incretin action on pancreatic cells is reduced

2

Less indirect

suppression

of glucagon

1. Kim W et al. Pharmacol Rev. 2008;60:470-512.


22

GLP-1 secreted upon

the ingestion of food

23 23

Glucose-Dependent Effects of GLP-1 Infusion on Insulin and Glucagon Levels in Patients With Type 2 Diabetes

Adapted with permission of Springer Verlag. Adapted from Nauck MA et al. Diabetologia. 1993;36(8):741–744. Copyright © 1993 Springer

Verlag. Permission conveyed through Copyright Clearance Center, Inc.

Glucose

Glucagon When glucose levels

approach normal values,

glucagon levels rebound.

When glucose levels

approach normal values,

insulin levels decrease.

*P<0.05

Patients with

type 2 diabetes (N=10)

mm

ol/

L 15.0

12.5 10.0

7.5 5.0

250

200

150

100

50

mg

/dL

* *

* * * * *

pm

ol/

L 250

200 150 100

50

40

30

20

10

0

mU

/L

* * * * * * *

*

Infusion

Minutes

pm

ol/

L 20

15

10

5

0 60 120 180 240

* * * *

pm

ol/L

20

15

10

5

Placebo

GLP-1

Insulin

2.5 0

0

0 0

0

–30

24

Incretins Play an Important Role in Glucose Homeostasis

1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913.

2. Ahrén B. Curr Diab Rep. 2003;2:365–372.

3. Drucker DJ. Diabetes Care. 2003;26:2929–2940.

4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441.

Insulin from beta cells

(GLP-1 and GIP)

Glucagon from

alpha cells

(GLP-1)

Release of gut

hormones—

Incretins1,2

Pancreas2,3

Glucose Dependent

Active

GLP-1 & GIP

DPP-4

enzyme

Inactive

GIP

Inactive

GLP-1

Glucose Dependent

↓ Blood

glucose GI tract

↓Glucose

production

by liver

Food ingestion

↑Glucose uptake by peripheral tissue2,4

Beta cells

Alpha cells

25

Blood

glucose

Inactive

GIP

Inactive

GLP-1

DPP-IV inhibitor Targets 2 Physiologic Glucose-Lowering Actions With a Single Oral Agent

Insulin

(GLP-1 and GIP)

Glucagon

(GLP-1)

Release of

active incretins

GLP-1 and GIP

Pancreas

Glucose dependent

DPP-4

enzyme

Glucose dependent

GI tract

Food ingestion

X DPP-4 inhibitor

• Incretin hormones GLP-1 and GIP are released by the intestine throughout the day;

their levels increase in response to a meal.

• Gliptins blocks DPP-4 to enhance the level of active incretins for 24 hours.

Beta cells

Alpha cells

Glucose

production

by liver

Glucose

uptake by

peripheral tissue

X

26

Alpha-

Glucosidase

Inhibitors1,2

Meglitinides3 SUs4,5 TZDs6,7

Metformin8

DPP-4

Inhibitors

Insulin

deficiency

Insulin

resistance

Excess hepatic

glucose output Ma

jor

Pa

tho

ph

ysio

log

ies

1. Glyset [package insert]. New York, NY: Pfizer Inc; 2004. 2. Precose [package insert]. West Haven, Conn: Bayer; 2004.

3. Prandin [package insert]. Princeton, NJ: Novo Nordisk; 2006. 4. Diabeta [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2007.

5. Glucotrol [package insert]. New York, NY: Pfizer Inc; 2006. 6. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals; 2004.

7. Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005.

8. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004.

Intestinal

glucose

absorption

No Single Class of Oral Antihyperglycemic Monotherapy Targets All Key Pathophysiologies

27

*High risk patients are those with acute coronary syndromes or previous cardiovascular events.

AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; ADA = American Diabetes Association; EASD = European Association for the Study of Diabetes; HDL = high-density lipoprotein; LDL = low-density lipoprotein.

1. ADA Standards of Medical Care in Diabetes – 2009. Diabetes Care. 2009;32:S13–S61.

2. American Association of Clinical Endocrinologists. Endocrine Practice. 2007;13(suppl 1):3–68.

Management of Type 2 Diabetes

•Type 2 diabetes requires a multifactorial approach for the management of glucose levels, blood pressure, and lipids to reduce complications1

•Recommendations for type 2 diabetes:

Lifestyle

Modification Hypertension

Dyslipidemia:

LDL

Dyslipidemia:

HDL HbA1c Goal

Combination

therapy within

3 mo if not at

HbA1c goal

ADA/EASD1 Target

<130/80

mmHg

Target LDL

<100 mg/dL (<70 mg/dL for high-

risk patients*)

Target HDL >40

mg/dL in men,

>50 mg/dL in

women

<7%

ACE/AACE2 Target

<130/80

mmHg

Target LDL

<100 mg/dL (<70 mg/dL for high-

risk patients*)

Target HDL >40

mg/dL in men,

>50 mg/dL in

women

≤6.5%

28

United Kingdom Prospective Diabetes Study (UKPDS)

Conventional Monotherapies Unable to Maintain Glycemic Control Over Time

Med

ian

A1C

(%

)

Time from randomization (years)

Glibenclamide (glyburide)

Conventional*

Insulin

MET

0

6

7

8

10

0 3 6

9

9 12 15

ADA Goal

AACE Goal

FPG = fasting plasma glucose; MET = metformin. *Conventional therapy defined as dietary advice given at 3-month intervals where FPG was targeted at best levels feasible in clinical practice. If FPG exceeded 270 mg/dL, patients were re-randomized to receive nonintensive MET, chlorpropamide, glibenclamide, or insulin. If FPG exceeded 270 mg/dL again, those on SU would have MET added. If FPG exceeded 270 mg/dL after this, insulin was substituted. Adapted from UK Prospective Diabetes Study (UKPDS 34) Group. Lancet. 1998;352:854–865.

29 29

OAD=oral antidiabetic agent.

Adapted from Del Prato S et al. Int J Clin Pract. 2005;59(11):1345–1355. Copyright © 2005. Adapted with permission of Blackwell Publishing Ltd.

Published Conceptual

Approach

Earlier and More Aggressive Intervention May Improve Patients’ Chances of Reaching Goal

A1

C G

oa

l

Mean A1C

of patients Duration of Diabetes

OAD

monotherapy

Diet and

exercise

OAD

combination

OAD

up-titration

OAD +

multiple daily

insulin

injections

OAD +

basal insulin

Conventional stepwise treatment approach

Earlier and more aggressive intervention approach

6

7

8

9

10

30

Glucose

absorption

Hepatic glucose

overproduction

Beta-cell

dysfunction

Insulin

resistance

Major Targeted Sites of Oral Drug Classes

DPP-4=dipeptidyl peptidase-4; TZDs=thiazolidinediones.

DeFronzo RA. Ann Intern Med. 1999;131:281–303.

Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483.

Pancreas

↓Glucose level

Muscle

and fat Liver

Biguanides

TZDs Biguanides

Sulfonylureas

Meglitinides

TZDs

Alpha-

glucosidase

inhibitors

Gut

The glucose-dependent

mechanism of DPP-4 inhibitors

targets 2 key defects: insulin

release and unsuppressed

hepatic glucose production.

DPP-4 inhibitors

DPP-4 inhibitors

Biguanides

31

31

Percentage of patients

with increase in antibodies

Liraglutide1

0

20

40

60

80

100

Exenatide +

metformin2

8.6%

43%

97% amino acid

homology to

human GLP-1

53% amino acid

homology to human

GLP-1 • There was no

blunting of efficacy

by liraglutide antibodies

Study duration: liraglutide 26 weeks; exenatide 30 weeks.

1. Clinical Trial Program meta-analysis of antibody formation; Data on file. Novo Nordisk Inc., Princeton, NJ. 2. DeFronzo et al. Diabetes

Care. 2005;28:1092.

Native human GLP-1

Liraglutide

Exenatide

Native Human GLP-1, Liraglutide & Exenatide

32

32

Liraglutide: First-Phase Insulin Secretion and Maximal Beta-Cell Insulin Secretory Capacity

Mean clamp profiles

for insulin

Co

nce

ntr

ation

(p

mo

l/L

)

89

328

567

805

1044

1283

1522

1761

1999

2238

2477

2716

Time (min)

0 15 30 45 60 75 90 105 135 150

Figure 8.1

Mean First Phase Insulin

(Clamp) Profiles C

on

ce

ntr

atio

n (

pm

ol/L

)

89

104

119

135

150

165

180

195

211

226

241

256

0 2 4 6 8 10 12 14 16 18 20

First-phase insulin

response

Maximal beta-cell

secretory capacity

Arginine

bolus

As measured by first-phase insulin response and maximal beta-cell secretory capacity. Mean insulin profiles during glucose

bolus (insert), hyperglycemic clamp, and arginine stimulation test.

Vilsbøll et al. Diabet Med. 2008;25:152–156.

Liraglutide

Placebo

33

Therapies for type 2 diabetes Glucose-lowering Potential

1. Riddle et al. Endocrinol Metab Clin N Am 2005;34:77–98. 2. Ahren et al. Diabetes Care 2002;25:869–75.

3. Ahren et al. J Clin Endocrinol Metab 2004;89:2078–84.

Therapy Fasting Glucose A1C

Incretins1 20–25 mg/dL Up to 1.0%

DPP4 inhibitors2,3 15-20 mg/dL 0.5–1.0%

Thiazolidinediones1 28–80 mg/dL 0.75–2.0%

Secretagogues1 30–70 mg/dL 1.5–2.0%

Metformin1 30–64 mg/dL 1.5–2.0%

Insulin > 100 mg/dL Unlimited

34

TYPE 2 DIABETES . . . A PROGRESSIVE DISEASE

Over time, most patients will need

insulin to control glucose

6-7

36

“If you do not get your sugars under control,

you will go on INSULIN !!!”

37

Types of insulin preparation

• Species of origin

– Animal (extracted porcine or bovine insulin)

– Human (bio-engineered)

– Modern/analog (bio-engineered)

• Duration of action

– Short-acting (Rapid Acting)

– Long-acting (Basal)

– Dual-acting (premixed or biphasic)

• Formulation

– Vials: 10 mL

– Cartridges: 1.5 mL and 3 mL

– Prefilled (disposable pens): 1.5 mL and 3 mL

38

Development of insulins

Modern Older

Animal Human Analog

Prandial /

Rapid Acting Novolin R, Humulin R,

Actrapid

Aspart, Lispro

Glulisine

Intermediate

-acting Novolin 70/30,

Humulin 70/30

Aspart Mix 70/30

Lispro Mix 75/25,

50/50

Basal Novolin N, Humulin N,

Lente

Levemir,

Glargine

39

Insulin Analogues

Human Insulin Dimers and hexamers

in solution

A-chain

B-chain

Lys Pro

Gly

Arg Arg

Asp

Lispro Limited self-aggregation

Monomers in solution

Aspart Limited self-aggregation


Glargine Soluble at low pH

Precipitates at

neutral (subcutaneous) pH

Glu Glulisine Limited self-aggregation


Lys

40

40

Mean free serum insulin concentrations were collected up to 6 hours following a single dose of NovoLog®

injected before a meal vs regular human insulin injected 30 minutes before a meal or immediately before

a meal in 22 patients with type 1 diabetes.

Adapted from Lindholm A et al. Diabetes Care. 1999;22:801-805.

Fre

e s

eru

m insulin

(munits/L

)

Time (h)

3 2 1 0 0

20

40

60

80

4 5 6

NovoLog® (immediately before a meal)

Physiologic insulin (theoretical)

Regular human insulin

(30 min before a meal)

NovoLog® Mimics the Body’s Normal Mealtime Insulin Response

Type 1

41

41

Pharmacokinetics of NovoLog® Mix 70/30 and Human Premix 70/30

Adapted from Weyer C et al. Diabetes Care. 1997;20:1612-1614.

Seru

m in

su

lin (

mu

nits/L

)

PPG phase

Hours after injection

4 8 12 16 20 24

35

25

15

0

Injection

5 FPG phase

NovoLog® Mix 70/30

Human premix 70/30

Single-center, randomized, double-blind, 24-hour crossover trial in 24 healthy male volunteers receiving 1 injection of

NovoLog® Mix 70/30 or human premix 70/30, 0.3 unit/kg; serum insulin concentrations were assayed every 30 minutes.

42

42

Two Basal Insulin Analogs: Two Mechanisms of Protraction

•Isoelectric point shifted

•Soluble at low pH, insoluble at pH 7

•Injected as solute, precipitates in subcutis

•Slow dissolution of precipitate

•Delayed and protracted absorption

•Soluble at pH 7

•Myristic acid side chains

•Increased hexamer stability

•Remains in solution after injection

•Delayed absorption

•Reversible albumin binding

•Buffers effect of absorption rate changes

Lispro

A1

s

A-chain

B-chain B1

A21

B30

s s

s

s s

Glycine replaces asparagine

Added arginine x2

A1

s

A-chain

B-chain B1

A21

B29

s s

s

s s

B30 threonine removed

Myristic acid attached

Insulin Glargine Levemir®

43

Levemir

A soluble, long-acting basal insulin analog with a relatively flat action profile

Lys

Pro Thr

Tyr Phe

Phe Arg Gly

B29

B30

Lys

Pro Thr

Tyr Phe

Phe Arg Gly

Glu

Glu Gly

Cys

Val

Leu

Tyr

Leu

Ala

Val

Leu

His

Ser

Gly

Cys

Glu

Glu Gly

Cys

Val

Leu

Tyr

Leu

Ala

Val

Leu

His

Ser

Gly

Cys

Val Phe Asn Gln Leu

His B1 Val Phe Asn Gln Leu

His B1

Thr

Gln

Tyr

Leu Ser Cys Ile Ser Cys Thr

Gln

Tyr

Leu Ser Cys Ile Ser Cys

Asn

Glu

Leu

Tyr Cys Asn

A21 Asn

Glu

Leu

Tyr Cys Asn

A21

Cys

Gln

Glu

Val

Ile

Gly A1

Cys

Gln

Glu

Val

Ile

Gly A1

B29 Thr

Acylation with myristic acid

Remains as solution after injection

Neutral pH

Duration of action is up to 24 hours

Albumin binding

44

Comparison of Human Insulins and Analogues

Insulin Onset of Duration of Preparations Action Peak Action

Lispro / Aspart / Glulisine 5-15 minutes 1-2 hours 4-6 hours

Human Regular 30-60 minutes 2-4 hours 6-10 hours

Human NPH/Lente 1-2 hours 4-8 hours 10-20 hours

Human Ultralente 2-4 hours Unpredictable 16-20 hours

Glargine / Levemir 1-2 hours Relatively Flat ~24 hours

6-22

45

Ideal Basal/Bolus Insulin Absorption Pattern

1. Skyler JS. In: Therapy of Diabetes Mellitus and Related Disorders. Lebovitz HE, ed. Alexandria, Va: ADA; 2004.

2. McCall AL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc; 2002:193-222.

Time

0

25

50

75

4:00 12:00 16:00 20:00 24:00 4:00 8:00 8:00

Plasma Insulin

(µU/mL)

Breakfast Lunch Dinner

46

Basal/Bolus Insulin Absorption Pattern with Standard Insulin Preparations

Breakfast Lunch HS

REG REG

Dinner

Time 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00

75

50

25

0

NPH

Intraprandial

hypoglycemia

Skyler J. In: Humes HD, Dupont HL, eds. Kelley’s Textbook of Internal Medicine. 4th ed.

Philadelphia, Pa: Lippincott; 2000.

Plasma

insulin

(U/mL)

47

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

Breakfast Lunch Dinner

8:00 12:00

Time

8:00

Twice-Daily Split-Mixed Regimens or LisproMix (75/25)-BiAspMix (70/30)

In

su

lin

Acti

on

Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342

48

* The abbreviations used here correspond to those used on the algorithm (Fig. 1).

** The term ‘glinide’ includes both repaglinide and nateglinide.

Benefits are classified according to major effects on fasting glucose, postprandial glucose, and nonalcoholic fatty liver disease (NAFLD). Eight

broad categories of risks are summarized. The intensity of the background shading of the cells reflects relative importance of the benefit or risk.*

Available at www.aace.com/pub

© AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE

49

Physician – Patient Relationship

(…..can tend to be a little bit judgmental…)

50

Take Home Message: Management of Type 2 Diabetes

• A1C reduction has been shown to reduce the risk of microvascular complications and may contribute to risk reduction of macrovascular endpoints1

• Early intervention is needed to get A1C to goal (diet and exercise should always be recommended)2

• It is challenging to maintain A1C control over time with traditional monotherapies3

• AACE and ADA* guidelines recommends use of combination therapy to achieve and sustain glycemic goals2,4

*ADA guidelines recommend that a second medication should be added within 3 months if patients are not at goal.

1. Stratton IM et al. BMJ. 2000;321:405–412; 2. American Diabetes Association. Diabetes Care. 2008;31(suppl 1):S12–S54; 3. UKPDS. Lancet. 1998;352:854–865; 4. AACE. Endocr Pract. 2007;13(suppl 1):4–68.

51

Take Home Message: Management of Type 2 Diabetes

• Pathophysiology involves, insulin resistance, beta & alpha cell dysfunction and increased hepatic glucose production.

• Analog insulins mimic physiology better and therefore allow for adequate titration to get to A1c goal without significant hypoglycemia and weight gain.

• There is a need to treat the whole patient, including management of hyperglycemia, CV risk factors and other comorbidities. This is key in reducing diabetes-related complications3

1. Kahn SE. J Clin Endocrinol Metab. 2001;86:4047–4058. 2. AACE. Endocr Pract. 2007;13(suppl 1):4–68.

3. Stratton IM et al. BMJ. 2000;321:405–412.

4. American Diabetes Association. Diabetes Care. 2008;31(suppl 1):S12–S54.

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