1

A Treatment Based Perspective

Pathophysiology of Type 2 Diabetes

2

Learning Objectives

• Review the pathophysiology of Type 2 Diabetes

Mellitus

• Compare the risks and benefits of oral

hypoglycemic agents in the management of Type

2 Diabetes Mellitus

• Discuss future potential new classes or oral

hypoglycemic agents

3

Adapted from Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355. Permission requested.

Published Conceptual Approach

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

7

8

6

9

10

A1C,

%

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

Diagnosis of Diabetes 2010-11 Simplified Screening and Detection

• A1C 6.5% (NGSP, DCCT* standard) – non-fasting test

– Fasting glucose 126 mg/dl (8 hour fast)

– 2 hour glucose 200 mg/dl during OGTT (WHO 75

g test)

• If symptoms of hyperglycemia = random glucose 200 mg/dl

PRE-DIABETES (IFG or IGT)

2-h PG > 200 2-h PG 140 – 199 (IGT)

2-h PG < 140

FPG > 126

FPG > 100 – 125 (IFG)

FPG < 100

DIABETES

NORMAL

A1c > 6.5% A1c 5.7 – 6.4%

A1c < 5.7%

American Diabetes Association. Diabetes Care 34 (Suppl 1), 2011

Glucose Control and Treatment - 2011

• Increasing number of treatments available

– 12 distinct classes of medication, unique

mechanisms

– Majority introduced since 1995

• Increasing numbers of diabetes patients

– Represents 10-20% of unique clinic visits

• Multidrug therapy generally required to achieve

targets

– More than 90% of individuals after 10 years

Supports the application of standardized guidelines

for treatment

ADA/EASD – AACE – Others

The Pathophysiology of Type 2 Diabetes

Relative insulin

deficiency

Insulin

resistance

Hyperglycemia

T2 diabetes and pre-diabetes

Adapted from Kendall DM, et al. Am J Med. 2009;122(6 Suppl):S37-50.

Relative insulin

deficiency

Insulin

resistance

2

The Pathophysiology of Type 2 Diabetes

Impaired

incretin effect

Relative insulin

deficiency

Insulin

resistance

Hyperglycemia

T2 diabetes and pre-diabetes

Adapted from Kendall DM, et al. Am J Med. 2009;122(6 Suppl):S37-50.

Incretins

• Gut hormones secreted from intestinal cells in

response to nutrient stimulus which have

favorable effects on glucose metabolism

• Major incretins in humans1,2:

– Glucagon-like peptide-1 (GLP-1)

– Glucose-dependent insulinotropic polypeptide

(GIP)

• Oral glucose elicits greater insulin response

than IV glucose (i.e. the “incretin effect”)

1Drucker DJ. Diabetes Educator. 2006;32(Suppl 2):65S-71S. 2Vilsbøll T, Holst JJ. Diabetologia. 2004;47:357-366.

Time, min

IR In

su

lin

, m

U/L

nm

ol/L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

180 60 120 0

The Incretin Effect

Control Subjects

(n=8)

Type 2 Diabetics

(n=14)

Time, min

IR In

su

lin

, m

U/L

nm

ol / L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

180 60 120 0

Oral glucose load Intravenous (IV) glucose infusion

Incretin

Effect

The incretin effect

is diminished

in type 2 diabetes.

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

Permission pending.

10

GLP-1 Modes of Action in Humans

GLP-1 is secreted

from the L-cells

in the intestine

This in turn…

• Stimulates glucose-dependent

insulin secretion • Suppresses glucagon secretion

• Slows gastric emptying

Long term effects demonstrated in animals…

• Increases -cell mass and

maintains -cell efficiency

• Improves insulin sensitivity

• Reduces food intake

Upon ingestion of food…

Drucker DJ. Curr Pharm Des 2001; 7:1399-1412

Drucker DJ. Mol Endocrinol 2003; 17:161-171

Mean (SE); *P < 0.05 GLP-1 = glucagon-like peptide-

1

Glucose-dependent Effects of GLP-1

Glucose (mg/dL) Insulin (pmol/L) Glucagon (pmol/L)

Type 2 Diabetes (n =

10)

Placeb

o GLP-1

270

180

90

0 -30 0 60 120 180 240

300

200

100

0 -30 0 60 120 180 240

20

10

0 -30 0 60 120 180 240

Time (min) Time (min) Time (min)

*

*

*

*

* * *

* * * *

* * *

*

* *

* *

Adapted from Nauck MA, et al. Diabetologia. 1993;36:741–744.

12

Glucoregulatory Role of Key Incretin Hormones

GLP-1

Inhibits gastric emptying1,2

Reduces food intake and

body weight2

Inhibits glucagon secretion from

alpha cells in a glucose-dependent

manner1

Stimulates insulin response from

beta cells in a glucose-dependent

manner1

Is released from L cells in ileum and

colon1,2

GIP

Has no significant effects on satiety

or body weight2

Does not affect gastric emptying2

Stimulates insulin response from

beta cells in a glucose-dependent

manner1

Is released from K cells in

duodenum1,2

GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic peptide.

1. Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606.

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

3

13

Intestinal

GLP-1

Release

GLP-1

Inactive

(~80% of pool)

GLP-1

Active

DPP-4

t1/2 = 1 to 2 min

Intestinal

GIP

Release

DPP-4i

DPP-4 Degrades GLP-1

Meal

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

DPP-4= dipeptidyl dipeptidase-4; GLP-1=glucagon-like peptide-1;

GIP=glucose insulinotropic peptide

DPP- 4 Inhibition and Plasma Levels of GLP-1

• DPP- 4 inhibition:

– Prevents the degradation of active GLP-1 levels

– Does not stimulate GLP-1 secretion

– Does not prevent the kidney from rapidly clearing

GLP-11-3

– Decreases secretion of GLP-1, likely via negative

feedback inhibition of the L cell3,4

• Sitagliptin, saxogliptin DPP-4 inhibitors approved

in U.S.5

1. Drucker DJ. Diabetes Care. 2007;30:1335-1343;

2. Herman GA, et al. J Clin Endocrinol Metab.2006; 91:4612-4619;

3. DPP-4: http://www.glucagon.com/dpp4.html. Updated June 9, 2008. Accessed June 25, 2008 4. Deacon DF, et al. J Endocrinology. 2002;172:355-362

Glu

co

se

(mg

/dL

)

bo

dy

weig

ht

Diabetes

diagnosis

50

100

150

200

250

300

350

Fasting glucose

Adapted from Kendall DM, et al. Am J Med. 2009;122(6 Suppl):S37-50.

Years

Rela

tive a

mo

un

t

-10 -5 0 5 10 15 20 25 30

Insulin resistance

Insulin level

Onset

High risk for diabetes

0

50

100

150

200

250

-15

Natural History of Type 2 Diabetes What Role Can Incretin-Based Therapy Play?

Post-meal glucose

Body weight

ADA/EASD Consensus Algorithm for the Initiation and Adjustment of Therapy

Diabetes Care 2009; 32:193–203

a - Sulfonylureas other than glybenclamide (glyburide) or chlorpropamide.

A1C 6.5 – 7.5%**

Monotherapy

MET +

GLP-1 or DPP4 1

TZD 2

Glinide or SU 5

TZD + GLP-1 or DPP4 1

MET + Colesevelam

AGI 3

2 - 3 Mos.***

2 - 3 Mos.***

2 - 3 Mos.***

Dual Therapy

MET +

GLP-1 or DPP4 1

+

TZD 2

Glinide or SU 4,7

A1C > 9.0%

No Symptoms

Drug Naive Under Treatment

INSULIN

± Other

Agent(s) 6

Symptoms

INSULIN

± Other

Agent(s) 6

INSULIN

± Other

Agent(s) 6

Triple Therapy

AACE/ACE Algorithm for Glycemic

Control Committee

Cochairpersons:

Helena W. Rodbard, MD, FACP, MACE

Paul S. Jellinger, MD, MACE

Zachary T. Bloomgarden, MD, FACE

Jaime A. Davidson, MD, FACP, MACE

Daniel Einhorn, MD, FACP, FACE

Alan J. Garber, MD, PhD, FACE

James R. Gavin III, MD, PhD

George Grunberger, MD, FACP, FACE

Yehuda Handelsman, MD, FACP, FACE

Edward S. Horton, MD, FACE

Harold Lebovitz, MD, FACE

Philip Levy, MD, MACE

Etie S. Moghissi, MD, FACP, FACE

Stanley S. Schwartz, MD, FACE

* 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 DPP4 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

MET +

GLP-1

or DPP4 1 ± SU 7

TZD 2

GLP-1

or DPP4 1 ± TZD 2

A1C 7.6 – 9.0%

Dual Therapy 8

2 - 3 Mos.***

2 - 3 Mos.***

Triple Therapy 9

INSULIN

± Other

Agent(s) 6

MET +

GLP-1 or DPP4 1

or TZD 2

SU or Glinide 4,5

MET +

GLP-1

or DPP4 1 + TZD 2

GLP-1

or DPP4 1 + SU 7

TZD 2

MET † DPP4 1 GLP-1 TZD 2 AGI 3

Available at www.aace.com/pub

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

AACE

What Makes Treatment Algorithms Successful?

• Evidence based (not solely on acquisition cost)

– Pathophysiologic basis for treatment

– Clinical evidence for treatment choice

• Customized, team-centered approach

– Clinicians – Educator – Pharmacist – Other health

professional

– Training support on use is essential

– Individualized to community, clinical setting

• Established treatment targets and timelines

– Updated on a regular basis

Hirsch IB. Diab Res Clin Pract 2002;58:27-36

Choi SH. Clinical Endocrinol 2008;69:549-555

Sperl-Hillen J. Diabetes 2003 (abstract)

4

Patient age

Disease duration

Comorbidities

Hypoglycemia risk

8.0% 7.0%

Behavioral – social - economic

Higher motivation, knowledge Greater self-care capacity, insight, support

Less motivated, non-adherent, Limited self-care capacity, insight support

Established Complications

None Early Micro Advanced Micro CV

Adapted from Ismael-Beigi F. Ann Intern Med. 2011;154(8):554-9.

6.0%

Individualizing Glycemic Targets in Diabetes

20

Therapeutic Options for Type 2 Diabetes Mellitus

Glucose Lowering Therapy: Diabetes Care 2011 and Beyond

1982-5 1995 2001 1922 1950’s 1996 2003

Sulfonylurea

Human insulin

Lispro

Glinides - AGI

Glargine

Animal insulin

Glitazones

Aspart

2005

Exenatide

Pramlintide

Detemir

Metformin

2007 2009 2011

HYPOGLYCEMIC THERAPY TISSUE EFFECT MULTIPLE TISSUES

Exubera

Sitagliptin

Saxagliptin

Cholesevelam

Liraglutide

Bromocriptine

Linagliptin

22

Major Targets of Oral Drug Classes

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

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

2. Buse JB et al. In: Williams Textbook of Endocrinology. 2003:1427–1483.

Pancreatic

Islet Cells

↓Glucose level

Muscle and Fat

Liver

Sulfonylureas

Meglitinides

Biguanides

TZDs TZDs

Biguanides

alpha-Glucosidase inhibitors

Gut

DPP-4 inhibitors

DPP-4 inhibitors

24

Insulin Secretagogues Sulfonylureas, Repaglinide, and Nateglinide

Riddle MC. Am Fam Physician. 1999;60:2613-2620; Wolffenbuttel et al. Drugs. 1995;50:263-288;

Horton ES et al. Diabetes Care. 2000;23:1660-1665; Hanefeld M et al. Diabetes Care. 2000;23:202-207;

Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: ADA; 1998

Mechanism of action Increase basal and/or postprandial insulin secretion

Efficacy depends upon Functioning -cells

Power Sulfonylureas, repaglinide: decrease A1C 1%–2%

Nateglinide: decreases A1C 0.5%– 1%

Dosing Sulfonylureas: Qd or BID

Repaglinide, nateglinide: TID or QID with meals

Side effects Weight gain, allergy (rare)

Main risk Hypoglycemia

25

Biguanides Metformin

Riddle MC. Am Fam Physician. 1999;60:2613-2620;

Cusi K et al. Diabetes Rev. 1998;6:89-131

Primary mechanism Decreases hepatic glucose of action production

Efficacy depends upon Presence of insulin

Power Decreases A1C 1%–2%

Dosing 2 or 3 times daily (metformin) 1 or 2 times daily (metformin XR)

Side effects Diarrhea, nausea

Main risk Lactic acidosis, need to

monitor Scr

5

All Cause Mortality (%) at 10 years

• Diet + Metformin 14.6%

• Diet + Sulf/Insulin 20%

• Diet alone 21.7%

– RRR 32.7% with metformin + diet vs. diet alone

– ARR 7.1%

– NNT 14

27

α-Glucosidase Inhibitors Acarbose and Miglitol

Mechanism of action Delay carbohydrate absorption

Efficacy depends upon Postprandial hyperglycemia

Power Decrease A1C 0.5%–1%

Dosing 3 times daily

Side effects Flatulence

Main risk Liver enzyme elevation (rare)

Riddle MC. Am Fam Physician. 1999;60:2613-2620;

Lebovitz HE. Endocrinol Metab Clin North Am. 1997;26:539-551

28

Glitazones (TZDs) Pioglitazone and Rosiglitazone

Mechanism of action Enhance tissue response to insulin

Efficacy depends upon Presence of insulin and resistance to its action

Power Decrease A1C 0.9%–1.6%

Dosing Once daily

Side effects Edema, weight gain, anemia

Main risk Congestive heart failure

Riddle MC. Am Fam Physician. 1999;60:2613-2620; Zinman B. Diabetes Obesity

Metab. 2001;3(suppl 1):S34-S43; Actos (pioglitazone hydrochloride) package insert;

Avandia (rosiglitazone maleate) package insert

TZD’s and Fractures ADA Annual Meeting 6/25/2010

• A retrospective analysis conducted by the Scottish Diabetes Research Network of more than 90% of all patients with diabetes in Scotland. About 144,000 patients met the study criteria, taking at least 1 oral antidiabetic agent but not insulin, during the 2000 to 2008 study period.

• Thiazolidinediones also elevate the risk of hip fracture in women by 1.9 times (P<0.001) and in men by 2.23 times ( P=0.016) for a combined hazard ratio of 1.98 (P<0.0001).

– “We calculate that up to 17% of all hip fractures in the diabetic population can be attributed to TZDs.”

DPP-4 Inhibitors

Advantages

• No hypoglycemia

• Weight neutral

• Rapid onset of action

• Able to use in renal

dysfunction

• Few side effects

• No drug interactions

• May preserve cells

Disadvantages

• New medications

• No long-term

studies

• Weight neutral

• Only physiologic

incretin levels

• ? waning efficacy

32

Mean

Ch

an

ge i

n A

1C

, %

c

aCompared with placebo. bLeast squares mean (LSM) adjusted for prior antihyperglycemic therapy status and baseline value. cDifference

from placebo. dCombined number of patients on sitagliptin or placebo. eP<0.001 overall and for treatment-by-subgroup interactions.

CI, confidence interval.

1. Raz I et al. Diabetologia. 2006;49:2564–2571.

2. Aschner P et al. Diabetes Care. 2006;29:2632–2637.

Mean baseline A1C: 8.0%

P < 0.001a

–0.6b

–1.0

–0.8

–0.6

–0.4

–0.2

0.0

–0.8b

Placebo-Adjusted Results

24-week monotherapy study2

(95% CI: –1.0, –0.6)

18-week monotherapy study1

(95% CI: –0.8, –0.4)

n=193

n=229

Inclusion criteria A1C: 7%–10%

Overall <8 ≥8–<9 ≥9 Baseline A1C, %

–1.4

–0.6 –0.7

–1.8

–1.6

–1.4

–1.2

–1.0

–0.8

–0.6

–0.4

–0.2

0.0

n=411d

n=239d

n=119d

Mean

Ch

an

ge i

n A

1C

, %

Prespecified pooled analysis at 18 weekse

–0.7

n=769d

Sitagliptin Monotherapy Studies: A1C Reductions

Study 021 and 023

6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

8.0 7.7 7.9 8.0 7.9 7.8

Adjusted Mean Change from Baseline in HbA1c

at Week 12: Low-Dose Cohort

Ad

jus

ted

me

an

ch

an

ge

in

Hb

A1

c (

%)

*

* P<0.007

*

* *

*

Saxagliptin

Placebo 2.5 mg 5 mg 10 mg 20 mg 40 mg

(n=67) (n=55) (n=47) (n=63) (n=54) (n=52)

Dose

Rosenstock, J. et al., Diabetes Obes Metab 2008;10:376-386.

Colesevelam

• Indicated as an adjunct to diet and exercise to

improve glycemic control in adults with type 2

diabetes mellitus

• Not for treatment of type 1 DM or DKA

• Mechanism of action uncertain

• Contraindications:

– History of bowel obstruction

– Serum triglycerides >500 mg/dL

– History of hypertriglyceridemia-induced

pancreatitis

Colesevelam: Efficacy

• Not studied as monotherapy or in combination

with incretins

• Not extensively studied in combination w/ TZDs

• Clinical trials with pre-existing diabetes therapy

– A1c reductions of 0.5-0.8% as add-on to

metformin, sulfonylurea, or insulin therapy

– Significant LDL-C reductions of 12.3-16.1% vs.

placebo

Bays HE, et al. Arch Intern Med. In press. Fonseca VA, et al. Diabetes Care. 2008; 31: 1479-1484.

Goldberg RB, et al. Arch Intern Med. 2008; 168: 1531-1540.

38 Colesevelam HCl Improves Glycemic Control and Reduces LDL Cholesterol in Patients With Inadequately

Controlled Type 2 Diabetes on Sulfonylurea-Based Therapy

• Significantly reduced A1C and LDL cholesterol in

patients with type 2 diabetes when added to a

sulfonylurea based therapy.

• Colesevelam therapy was safe and well tolerated in

this study.

• No patient reported a severe episode of

hypoglycemia, and none discontinued due to

hypoglycemia.

• Colesevelam did not result in weight gain.

Fonseca VA et al. Diabetes Care 31:1479-1484, 2008

39

Efficacy of Oral Antihyperglycemics Declines With Time

• A1C rises at ~0.2% to 0.3% yearly on stable

therapy

• This rate is the same as for diet alone,

sulfonylureas, and metformin

• -Cell function declines at the same rate with all

these treatments

• Combination treatments are routinely needed

UKPDS Group. Diabetes. 1995;44:1249-1258; Turner RC et al. JAMA. 1999;281:2005-2012

40

Secondary Failure of Monotherapy Overweight Patients in the UKPDS

Turner RC et al. UKPDS 49. JAMA. 1999;281:2005-2012

Percent with A1C <7% on monotherapy

Diet 23 12 11

Sulfonylureas 45 28 21

Metformin 44 34 13

3 years 6 years 9 years

7

41

Cumulative incidence of monotherapy failure (FPG> 180 mg/dL)

Kahn. SE, et al. N Engl J Med 2006;355:2427-43

42

Estimated Improvements in Glycemic Control

DeFronzo, et al. N Engl J Med 1995;333:541-549; Horton, et al. Diabetes Care. 1998;21:1462-1469; Coniff, et al.

Diabetes Care.

1995;18:817-824; Moses, et al. Diabetes Care 1999;22:119-124; Schneider, et al. Diabetes 1999; 48 (Suppl 1): A106;

Egan, et al. Diabetes 1999; 48 (Suppl 1):A117. Fonseca, et al. Diabetes 1999:48 (Suppl 1):A100.

Regimen HbA1c FBG

Sulfonylurea + metformin ~1.7% ~65 mg/dL

Sulfonylurea + troglitazone ~0.9-1.8% ~50-60 mg/dL

Sulfonylurea + pioglitazone ~1.2% ~50 mg/dL

Sulfonylurea + acarbose ~1.3% ~40 mg/dL

Repaglinide + metformin ~1.4% ~40 mg/dL

Pioglitazone + metformin ~0.7% ~40 mg/dL

Rosiglitazone + metformin ~0.8% ~50 mg/dL

Insulin + oral agents Open to Target Open to Target

COMBINATION THERAPY

43

Initial Combination Therapy With Sitagliptin Plus Metformin Study: A1C Results From Patients not

on Antihyperglycemic Therapy at Study Entry

LS

M C

ha

ng

e

Fro

m B

as

elin

e,

%

Study 036

–1.1

n=88

–1.1

n=90

–1.2

n=87

–1.6

n=100

–1.9

n=86

–2.0

–1.8

–1.6

–1.4

–1.2

–1.0

–0.8

–0.6

–0.4

–0.2

0

–0.2

n=83

Sitagliptin 50 mg + metformin 1,000 mg bid

Metformin 1,000 mg bid

Sitagliptin 50 mg + metformin 500 mg bid

Metformin 500 mg bid Sitagliptin 100 mg qd Placebo

LSM=least squares mean change.

Data available on request from Merck & Co., Inc.

44

Initial Combination Therapy With Sitagliptin Plus Metformin Study: Change in

Body Weight and Incidence of Hypoglycemia

Placebo

Sita

100

MF

500

bid

MF

1,000

bid

Sita

50 +

MF 500

bid

Sita

50 +

MF 1,000

bid

Hypoglycemia

n/N (%)

1/176

(0.6)

1/179

(0.6)

1/182

(0.5)

2/182

(1.1)

2/190

(1.1)

4/182

(2.2)

LSM Change

From Baseline, kg

–2

–1

0

1

167 184 178 175 179 175

Rates of Hypoglycemia in

Combination With Sitagliptin

Sitagliptin 50 mg + metformin 1,000 mg bid Metformin 1,000 mg bid Sitagliptin 100 mg qd

Sitagliptin 50 mg + metformin 500 mg bid Metformin 500 mg bid Placebo

Sita=sitagliptin; MF=metformin.

Goldstein B et al. Diabetes Care. 2007;30:1979–1987.

Glycemic Targets

Self-Management • Refer for diabetes education

• SMBG, food & activity

Nutrition and Activity • Refer for Medical Nutrition Therapy

• May lower A1C 1-2 %

SMBG pre-meal 70-120 mg/dL, post-meal <160

mg/dL

A1C < 7%

Emotional Health • Psychosocial support / motivation

• Assess for anxiety and/or depression

Advance/initiate drug treatment if not at target

METFORMIN If not tolerated or if contraindicated select initial

therapy from TWO DRUG THERAPY below

At Presentation

A1C 7-8.9%

FPG 150-200 mg/dL

RPG 200-300 mg/dL

Titrate to clinically effective dose Advance if not at target in 3 months

TWO DRUG THERAPY

Incretin Defect Insulin Deficiency Insulin Resistance

A1C 9-11%

FPG 201-300 mg/dL

RPG 301-350 mg/dL

Treatment of Type 2 Diabetes: Glycemic Control

© Copyright International Diabetes Center (IDC) 2009. From

www.internationaldiabetescenter.com

Add Sulfonylurea Glimepiride or Glipizide XL

Rapid glucose lowering

Long history of use

Lowest cost

Risk of hypoglycemia, weight gain

Add DPP-4 Inhibitor Sitagliptin – Saxagliptin

Linagliption

Well tolerated, simple oral

dosing

No hypoglycemia

Higher cost

Weight neutral

Add GLP -1 Agonist Exenatide - Liraglutide

Weight loss, no hypoglycemia

Injectable (pen)

Higher cost

GI side effects - nausea

Add PPAR Agonist Pioglitazone

Targets insulin resistance, CV risk

Improves lipids (HDL, TG)

Higher cost

Edema, weight gain, bone effects Advance if not at target in 3 months Titrate to clinically effective dose

THREE DRUG THERAPY

Add Background Insulin* or TZD, SU Add Background Insulin

or

TZD, DPP-4, GLP-1

Background & Mealtime (main meal) + Oral Agent(s)* Premixed Insulin + Sensitizer(s)*

MULTI-DOSE INSULIN THERAPY

* Limited published data for use of

insulin plus either DPP-4 inhibitor or

GLP-1 agonist

Add Background Insulin

or

SU, DPP-4, GLP-1 A1C >11%

FPG >300 mg/dL

RPG >350 mg/dL

Start

Background or

Premix Insulin +

Metformin

Background & Mealtime (all meals) + Sensitizer(s)*

Glu

co

se

(mg

/dL

)

bo

dy

weig

ht

Diabetes

diagnosis

50

100

150

200

250

300

350

Fasting glucose

Adapted from Kendall DM, et al. Am J Med. 2009;122(6 Suppl):S37-50.

Years

Rela

tive a

mo

un

t

-10 -5 0 5 10 15 20 25 30

Insulin resistance

Insulin level

Onset

High risk for diabetes

0

50

100

150

200

250

-15

Post-meal glucose

Body weight

Weight loss

& Activity Insulin

Incretin therapy

Secretagogue

Metformin

TZD

8

DCCT/EDIC: Incidence of Nonfatal MI, Stroke, or Death After median 8.5 years post-trial follow-up

Aggregate Endpoint 1997 2007

Any diabetes related endpoint RRR: 12% 9%

P: 0.029 0.040

Microvascular disease RRR: 25% 24%

P: 0.0099 0.001

Myocardial infarction RRR: 16% 15%

P: 0.052 0.014

All-cause mortality RRR: 6% 13%

P: 0.44 0.007

RRR = Relative Risk Reduction, P = Log

Rank

Legacy Effect of Earlier Glucose Control

After median 8.8 years post-trial follow-up

Aggregate Endpoint 1997 2007

Any diabetes related endpoint RRR: 32% 21%

P: 0.0023 0.013

Microvascular disease RRR: 29% 16%

P: 0.19 0.31

Myocardial infarction RRR: 39% 33%

P: 0.010 0.005

All-cause mortality RRR: 36% 27%

P: 0.011 0.002

RRR = Relative Risk Reduction, P = Log

Rank

Legacy Effect of Earlier Metformin Therapy

Glycemic Targets in Adults • Lowering of A1C to at or below 7%

– Significantly reduce risk of microvascular complications of diabetes

– Does not reduce the risk of CVD events in short term studies

– But does not significantly increase mortality

– If initiated soon after diagnosis, possible long-term reduction in CVD

• Analysis suggest a small (but incremental) benefit in microvascular outcomes with A1C values closer to normal

– Later use of intensive treatment may reduce the magnitude of impact

Individualization of treatment critical

Skyler JS. Diabetes Care. 2009;32(1):187-92

ADA. Diabetes Care. Diabetes Care 2011;34 (suppl 1):S19.

Diabetes and Glycemic Control A Rational Approach to A1C Targets

As low as possible

As early as possible

For as long as possible

As safely as possible

And as rationally as possible

Everything should be made as simple as possible, but no simpler…

Treatment Targets for Adults with Diabetes

Minimizing Micro and Macrovascular Disease Risk

Measures

• A1C

– Pre-meal glucose

– Peak post-meal glucose

• Blood Pressure

• LDL-c

– Triglycerides

– HDL-c

Targets

< 7%

90 – 130 mg/dl

< 180 mg/dl

< 130/80 mm Hg

< 100 mg/dl

< 150 mg/dl

> 40 mg/dl

American Diabetes Association. Diabetes Care 34 (Suppl 1), 2011

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