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KAPA Annual ConferenceKAPA Annual ConferenceOctober 14, 2010October 14, 2010

Ellen D. Mandel, DMH, MS, PA-C, RD, CDEEllen D. Mandel, DMH, MS, PA-C, RD, CDEAssociate Professor, Seton Hall UniversityAssociate Professor, Seton Hall University

South Orange, NJSouth Orange, NJ

Physician Assistant, Evening PracticePhysician Assistant, Evening PracticeSummit Medical Group, Berkeley Heights, NJ Summit Medical Group, Berkeley Heights, NJ

Faculty DisclosuresFaculty Disclosures

Ellen D. Mandel, DMH, MS, PA-C, RD, CDEEllen D. Mandel, DMH, MS, PA-C, RD, CDE Nothing to disclose Does not intend to discuss any unapproved/

investigational use of a commercial product

Learning ObjectivesLearning Objectives

Upon completion of this activity, PAs should be better able to: Explain the relationship between excess body fat and cardio-

vascular disease (CVD) with type 2 diabetes mellitus (T2DM). Recognize the need for early and individualized management

of T2DM, given the progressive loss of beta-cell function that occurs years before diagnosis.

Differentiate among pharmacologic therapies for T2DM that target specific glycemic patterns and/or metabolic defects to achieve and maintain optimal glycemic control.

Integrate current guidelines into daily clinical practice. Implement strategies to achieve postprandial glucose control

with a goal to reduce risk for CVD.

AgendaAgenda

Snapshot: Type 2 Diabetes Today Clinical Implications of Lack of Glycemic Control Typical Management of Type 2 Diabetes Early Intervention for Optimal Glycemic Control

The State of Diabetes in AmericaThe State of Diabetes in America

Who is affected?– An estimated 24 million Americans—~8% of the population– Most have type 2 diabetes – About 40 million people 20 years old have IFG or IGT (pre-diabetes)

What is the impact?– 3 of 5 patients suffer from a complication of the disease– $174 billion in 2007 for direct ($116 billion) and indirect

($58 billion) costs 2 of 3 patients with type 2 diabetes do not meet HbA1C

treatment targets

8% of US population has diabetes

AACE. Available at: www.aace.com/public/awareness/stateofdiabetes. Accessed May 7, 2009.

CDC. Available at: http://apps.nccd.cdc.gov/DDTSTRS. Accessed May 7, 2009.Cowie CC et al. Diabetes Care. 2009;32:287-294.

IFG = impaired fasting glucose; IGT = impaired glucose tolerance

Both FPG and 2-h PPG Predict Mortality Both FPG and 2-h PPG Predict Mortality in Persons Not Known to Have Diabetesin Persons Not Known to Have Diabetes

DECODE Study Group. Lancet. 1999;354:617-621.

FPG = fasting plasma glucose; PPG = postprandial glucose; HR = hazard ratio

1.00

1.21

1.761.86

0.0

0.5

1.0

1.5

2.0

2.5

< 110 110 - 125 126 - 140 > 140

Adju

sted

HR

for M

orta

lity

1.00

1.59

2.00

0.0

0.5

1.0

1.5

2.0

2.5

< 140 140 - 200 > 200

All Subjects (N ≈ 25,000) Subjects With FPG <110 mg/dL

FPG (mg/dL) 2-h PPG (mg/dL)

HbAHbA1C1C as a Predictor of CHD as a Predictor of CHD in Type 2 Diabetesin Type 2 Diabetes

0

5

10

15

20

25

Kuusisto J et al. Diabetes. 1994;43:960-967.

†

*P<0.01 vs lowest tertile; †P<0.05 vs lowest tertileCHD = coronary heart disease

CHD Mortality All CHD Events

Inci

denc

e in

3.5

Yea

rs (%

)

Low (<6.0%)Middle (6.0%-7.9%)High (>7.9%)

*

Diabetes Has an Adverse Impact Diabetes Has an Adverse Impact on Quality of Lifeon Quality of Life

Macrovascular and microvascular consequences = long-term complications of diabetes

Toll of diabetes-related complications in US: – 71,000 nontraumatic lower-limb amputations (2004)

– 12,000 to 24,000 new cases of blindness each year

– Causes 44% of new cases of kidney failure (2005)

– 233,619 deaths from complications of diabetes (2005)

CDC. Available at: http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf. Accessed May 7, 2009.

Prevalences of Obesity and Diabetes Prevalences of Obesity and Diabetes Continue to Rise: NHANES DataContinue to Rise: NHANES Data

CDC. Health, United States, 2008. Available at: http://www.cdc.gov/nchs/data/hus/hus/08.pdf.

0

5

10

15

20

25

30

35

40

BMI = body mass index; NHANES = National Health and Nutrition Examination Survey

0

2

4

6

8

Obesity (BMI 30 kg/m2) Physician-diagnosed Diabetes

Perc

enta

ge o

f Pop

ulati

on

1988-1994 1999-2002 2003-2006 1988-1994 1999-2002 2003-2006

Are We Achieving Glycemic Control?Are We Achieving Glycemic Control?NHANES 1999-2004NHANES 1999-2004

1999-20001999-2000(N = 403)(N = 403)

2001-20022001-2002(N = 448)(N = 448)

2003-20042003-2004(N = 482)(N = 482)

Mean HbA1C 7.82 7.47 7.18

Patients with HbA1C <7% 36.9% 49.4% 56.8%

More than 40% of patients with diabetesMore than 40% of patients with diabetesdo not have adequate glycemic controldo not have adequate glycemic control

Hoerger TJ et al. Diabetes Care. 2008;31:81-86.

How Does HbAHow Does HbA1C1C Translate Translate to Glucose Levels?to Glucose Levels?

HbAHbA1C1C Level (%) Level (%) Blood Glucose Level (mg/dL)Blood Glucose Level (mg/dL)

55 9797

66 126126

77 154154

88 183183

99 212212

1010 240240

1111 269269

1212 298298

Nathan DM et al. Diabetes Care. 2008; 31:1473-1478.

Average Estimated Glucose (mg/dL) = 28.7 x HbA1C – 46.7

AgendaAgenda

Type 2 Diabetes Today Clinical Implications From Lack of Glycemic Control Typical Management of Type 2 Diabetes Early Intervention for Optimal Glycemic Control

DeFronzo RA. Pathogenesis of type 2 diabetes: implications for metformin. Drugs. 1999;58(suppl 1):29-30.

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

350350

300300

250250

200200

350350

100100

5050

350350

300300

250250

200200

350350

100100-15-15 -10-10 -5-5 00 55 1010 1515 2020 2525 3030

YearsYearsONSETONSET

Pre-diabetes (IFG, IGT)Pre-diabetes (IFG, IGT)Metabolic SyndromeMetabolic Syndrome

DiabetesDiabetesDiagnosisDiagnosis Insulin ResponseInsulin Response

Insulin ResistanceInsulin Resistance

Fasting GlucoseFasting Glucose

Post-meal GlucosePost-meal GlucoseObesity – InactivityObesity – Inactivity

GeneticsGenetics

Rela

tive

Func

tion

Rela

tive

Func

tion

Glu

cose

(mg/

dLG

luco

se (m

g/dL

0

10

20

30

40

Can Type 2 Diabetes Be Prevented or Delayed?Can Type 2 Diabetes Be Prevented or Delayed?Diabetes Prevention Program (DPP)Diabetes Prevention Program (DPP)

Diabetes Prevention Program Research Group. N Engl J Med. 2002;346(6):393-403.

0

5

10

15

-31% vs placebo

-58% vs placebo

Placebo Metformin Lifestyle

Ove

rall

Inci

denc

e of

Dia

bete

s (%

)

PlaceboMetforminLifestyle

0 0.5 1 1.5 2 2.5 3 3.5 4Year

Cum

ulati

ve In

cide

nce

of D

iabe

tes

(%)

PlaceboMetforminLifestyle

Type 2 Diabetes Characterized by a Type 2 Diabetes Characterized by a Progressive Decline in Progressive Decline in -Cell Function-Cell Function

Years From Diagnosis

-Ce

ll fu

nctio

n (%

)

PostprandialHyperglycemia

IGTType 2DiabetesPhase I

Type 2DiabetesPhase II

Type 2 DiabetesPhase III25

100

75

00

50

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

Lebovitz H. Diabetes Rev. 1999;7:139-153.

Causes of β-cell Failure• Reduction of β-cell mass

– Apoptosis– Decreased

proliferation– Amyloid deposition

• Glucotoxicity• Lipotoxicity• Decreased incretin effect

•UKPDS Extrapolation

Recommended Standard-of-Care Targets Recommended Standard-of-Care Targets for Patients With Type 2 Diabetesfor Patients With Type 2 Diabetes

ADAADA AACEAACE HbAHbA1C1C <7.0%<7.0% 6.5%6.5%

Preprandial plasma glucosePreprandial plasma glucose 90–130 mg/dL90–130 mg/dL <110 mg/dL<110 mg/dL

Peak postprandial glucosePeak postprandial glucose <180 mg/dL<180 mg/dL <140 mg/dL<140 mg/dL

Blood pressureBlood pressure <130/80 mm Hg<130/80 mm Hg

LDL-CLDL-C <100 mg/dL<100 mg/dL

TriglyceridesTriglycerides <150 mg/dL<150 mg/dL

HDL-CHDL-C >40 mg/dL (male)>40 mg/dL (male)>50 mg/dL (female)>50 mg/dL (female)

ADA. Diabetes Care. 2009;32(suppl 1):S13-S61; AACE. Endocr Pract. 2007;13(suppl 1):4-68.

ADA = American Diabetes Association; AACE = American Association of Clinical Endocrinologists; LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol

Are Patients With Diabetes Meeting Are Patients With Diabetes Meeting ADA Clinical Practice Guidelines?ADA Clinical Practice Guidelines?

Resnick HE et al. Diabetes Care. 2006;29:531-537.

BP = blood pressure

>45 mg/dL (men)>55 mg/dL (women)

0

20

40

60

80

100

39.6 +2.7

27.4 +2.036.0 +4.06

49.8 +3.68

NHANES 1999-2002 (N = 998)

HbA1C <7% LDL-C <100 mg/dL

HDL-C BP <130/80 mm Hg

Mee

ting

Reco

mm

ende

d G

oals

(%)

Does Glycemic Control Reduce Risk for Does Glycemic Control Reduce Risk for Diabetes-Related Complications? UKPDSDiabetes-Related Complications? UKPDS

Every 1% reduction in HbAEvery 1% reduction in HbA1C1C translates to: translates to:Risk Risk

ReductionReduction ComplicationComplication PP Value Value

43%43% Amputation or death from PVDAmputation or death from PVD <0.0001<0.0001

37%37% MicrovascularMicrovascular <0.0001<0.0001

21%21% Any diabetes-related end pointAny diabetes-related end point <0.0001<0.0001

21%21% Diabetes-related deathDiabetes-related death <0.0001<0.0001

14%14% Fatal or nonfatal MIFatal or nonfatal MI <0.0001<0.0001

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

UKPDS = United Kingdom Prospective Diabetes Study; MI = myocardial infarction; PVD = peripheral vascular disease

Microvascular Complications Increase Microvascular Complications Increase as HbAas HbA1C1C Increases: DCCT Increases: DCCT

1

3

5

7

9

11

13

15

Skyler J. Endocrinol Metab Clin North Am. 1996;25:243; DCCT Research Group. N Engl J Med. 1993;329:977.

DCCT = Diabetes Control and Complications Trial

6 7 8 9 10 11 12

HbA1C (%)

Rela

tive

Risk

Retinopathy

Nephropathy

Neuropathy

Microalbuminuria

Younger Patients With Type 2 Diabetes Have Younger Patients With Type 2 Diabetes Have Increased Risk for MorbidityIncreased Risk for Morbidity

Patients with diabetes 18 to 44 years old are: 14 times more likely to have MI 30 times more likely to have STROKE 80% more likely to need insulin 2 years of diagnosis

Hillier TA, Pedula KL. Diabetes Care. 2003;26:2999-3005. •N=7800 newly diagnosed DM

Patients With Type 2 Diabetes Patients With Type 2 Diabetes Have Reduced Life ExpectancyHave Reduced Life Expectancy

Venkat Narayan KM et al. JAMA. 2003;290:1884-1890.

QALY = quality-adjusted life years

Men Women

-30

-25

-20

-15

-10

-5

0

-17.2

-14.5

-11.6

-7.3

-17.9-16.5

-14.3

-9.5

-27.4

-23.1

-18.6

-11.1

-29.6

-26.1

-22

-13.8

20 30 40 60 20 30 40 60

Age at Diagnosis (y)

Life Years LostQALYs Lost

Year

s

NHANES 1984-2002

AgendaAgenda


Therapeutic Options in Type 2 DiabetesTherapeutic Options in Type 2 Diabetes

Therapeutic lifestyle changes (TLCs)

Metformin Sulfonylureas

(secretagogues) Glinides α-glucosidase

inhibitors

TZDs Insulin GLP-1 agonists

(exenatide) DPP-IV inhibitors

(sitagliptin, saxagliptin) Amylin agonists

(pramlintide)*

TZD = thiazolidinedione, GLP = glycoprotein, DPP = dipeptidyl peptidase*Approved in US only for use in combination with insulin

Nathan DM et al. Diabetes Care. 2009;32:193-203.

Basal and Preprandial InsulinBasal and Preprandial Insulin

Conventional Management Conventional Management of Type 2 Diabetesof Type 2 Diabetes

Three OADsThree OADs Two OADs + InsulinTwo OADs + Insulin

Add Second OADAdd Second OAD

Diet + ExerciseDiet + Exercise+ +

One OADOne OAD

Add InsulinAdd Insulin

OAD = oral antidiabetic drug



Tier 1: Well-validated core therapies

TLCs + Metformin+

PioglitazoneNo hypoglycemia

Edema/CHFBone loss

TLCs + Metformin+

GLP-1 agonistNo hypoglycemia

Weight lossNausea/vomiting

At diagnosis:TLCs

+Metformin

TLCs + Metformin+

Basal insulin

TLCs + Metformin+

Sulfonylurea

TLCs + Metformin+

Intensive insulin

STEP 1 STEP 2

TLCs + Metformin+

Basal insulin

TLCs + Metformin+

Pioglitazone+

Sulfonylurea

STEP 3

ADA/EASD Consensus ADA/EASD Consensus Treatment AlgorithmTreatment Algorithm

EASD = European Association for the Study of Diabetes

Tier 2: Less well-validated therapies

Scientific Evidence: Treatment Is Beneficial Scientific Evidence: Treatment Is Beneficial to Reduce Complicationsto Reduce Complications

UKPDS and DCCT: reducing HbA1C lowers risk for complications Meta-analysis (before ACCORD):

– Intensified glycemic control = 19% reduced macrovascular risk– Effect due to reductions in stroke and PVD events (42% each)– 9% reduction in cardiac events

ACCORD and ADVANCE– Early intervention is better– Not sufficiently powered for CV end points– ACCORD: higher mortality with intensive treatment

ACCORD = Action to Control Cardiovascular Risk in Diabetes; ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation

UKPDS 33. Lancet. 1998;352:837-853; DCCT. N Engl J Med. 1993;329:977-986; Stettler C et al. Am Heart J. 2006;152:27-38; ACCORD Study Group. N Engl J Med. 2008;358:2545-2559; ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572.

ACCORD vs ADVANCE: ACCORD vs ADVANCE: Studies of Intensive Glycemic ControlStudies of Intensive Glycemic Control

ACCORDACCORD(N = 10,251)(N = 10,251)

ADVANCEADVANCE(N = 11,140)(N = 11,140)

Mean ageMean age 62 y62 y 66 y66 y

Mean duration of diabetesMean duration of diabetes 10 y10 y 8 y8 y

Median HbAMedian HbA1C1C at entry at entry 8.1%8.1% 7.2%7.2%

Target HbATarget HbA1C1C <6%<6% <6.5%<6.5%

Duration of treatmentDuration of treatment 3.5 y3.5 y 5 y5 y

Median HbAMedian HbA1C1C at study end at study end(intensive vs conventional treatment)(intensive vs conventional treatment) 6.4% vs 7.5%6.4% vs 7.5% 6.4% vs 7.0%6.4% vs 7.0%

Outcome risk for all-cause mortalityOutcome risk for all-cause mortality HR 1.22HR 1.22((P P = 0.04)= 0.04)

HR 0.93HR 0.93((P P = 0.28)= 0.28)

ACCORD. N Engl J Med. 2008;358:2545-2559; ADVANCE. N Engl J Med. 2008;358:2560-2572.

Type 2 Diabetes and CVD Risk Reduction: Lessons Type 2 Diabetes and CVD Risk Reduction: Lessons From ADVANCE, ACCORD, VADT, and UKPDSFrom ADVANCE, ACCORD, VADT, and UKPDS

Prevent early microvascular complications through better glycemic control

Individualize glucose goals for patients with advanced CVD

– Close to 7%, not necessarily <7%, in high-risk elderly

For early type 2 diabetes without advanced CVD:– Use more intense glycemic control to modestly reduce CVD risk

– An HbA1C target 6.5% may be appropriate

ACCORD. N Engl J Med. 2008;358:2545-2559; ADVANCE. N Engl J Med. 2008;358:2560-2572; Duckworth W et al. N Engl J Med. 2009;360:129-139; UKPDS 33. Lancet. 1998;352:837-853.

VADT = Veterans Affairs Diabetes Trial

TREAT TYPE 2 DIABETES EARLYTREAT TYPE 2 DIABETES EARLY

Type 2 Diabetes and CVD Risk Reduction: Lessons Type 2 Diabetes and CVD Risk Reduction: Lessons From ADVANCE, ACCORD, VADT, and UKPDS From ADVANCE, ACCORD, VADT, and UKPDS (cont’d)(cont’d)

Avoid hypoglycemia, especially in known/suspected CVDFocus on other CVD risk factors through:

– Lipid-lowering

– BP reduction

– Anti-platelet therapy

– Smoking cessation

– Antihyperglycemic agents

ACCORD. N Engl J Med. 2008;358:2545-2559; ADVANCE. N Engl J Med. 2008;358:2560-2572; Duckworth W et al. N Engl J Med. 2009;360:129-139; UKPDS 33. Lancet. 1998;352:837-853.

BP = blood pressure

TREAT TYPE 2 DIABETES EARLYTREAT TYPE 2 DIABETES EARLY

AgendaAgenda


Case in Point: IsabelCase in Point: Isabel

Latina, age 30 History of gestational diabetes mellitus “Social” smoker BMI: 29 kg/m2 (overweight) BP: 140/80 mm Hg Lipids:

– Total cholesterol = 204 mg/dL– LDL-C = 138 mg/dL

FPG: 118 mg/dL Order 2-h OGTT and HbA1C

Does Isabel haveDoes Isabel havepre-diabetes?pre-diabetes?

OGTT = oral glucose tolerance test

– HDL-C = 30 mg/dL– Triglycerides: 180 mg/dL

ADA Pre-Diabetes Decision TreeADA Pre-Diabetes Decision Tree

Identify patients at high risk for pre-diabetesIdentify patients at high risk for pre-diabetes

Obtain FPG or OGTT for all high-risk patients Obtain FPG or OGTT for all high-risk patients

FPGFPG OGTTOGTT

100-125 mg/dL100-125 mg/dLPre-diabetesPre-diabetes

>>126 mg/dL126 mg/dLDiabetesDiabetes

140-199 mg/dL140-199 mg/dLPre-diabetesPre-diabetes

>>200 mg/dL200 mg/dLDiabetesDiabetes

ADA. Diabetes Care. 2009;32(Suppl 1):S13-S61.

ADA Recommended Standard of Care ADA Recommended Standard of Care for Pre-Diabetesfor Pre-Diabetes

Monitor for development of diabetes annually Individualized medical nutrition therapy Weight loss of 5% to 10% Moderate physical activity (~30 min/day for

5 days/wk)

ADA. Diabetes Care. 2007;30(suppl 1):S4-S41.

ADA Recommended Standard of Care ADA Recommended Standard of Care for Pre-Diabetes for Pre-Diabetes (cont’d)(cont’d)

Consider metformin treatment for:– Patients at very high risk for developing diabetes

Combined IFG and IGT

HbA1C >6%

Hypertension

Low HDL-C

Elevated triglycerides

Family history in 1° relative

– Obese patients

– Patients <60 years old

ADA. Diabetes Care. 2007;30(suppl 1):S4-S41.

Lifestyle Modification Can Reduce Incidence Lifestyle Modification Can Reduce Incidence of Type 2 Diabetes by >50%of Type 2 Diabetes by >50%

DPP. N Engl J Med. 2002;346:393-403.

0

5

10

15

↓31%*

↓58%*†

*P<0.001 vs placebo†P<0.001 vs metformin

Diabetes Prevention Program (N = 3234)

7.87.84.84.8

11.011.0

PlaceboPlacebo Metformin Metformin (850 mg BID)(850 mg BID)

Lifestyle Lifestyle ModificationModification

((>>7% weight loss,7% weight loss,>>150 min activity/wk)150 min activity/wk)

Inci

denc

e of

Typ

e 2

Dia

bete

s (c

ases

/100

per

son-

year

s)

Isabel: Follow-up Laboratory TestsIsabel: Follow-up Laboratory Tests

Repeat FPG: 122 mg/dL 2-h 75-g OGTT results:

– Fasting glucose level = 120 mg/dL

– 2-h glucose level = 233 mg/dL

HbA1C = 7.3%

Isabel has Isabel has clinical diabetesclinical diabetes

Isabel: Treatment DecisionsIsabel: Treatment Decisions

Therapeutic lifestyle changes (TLCs)

Metformin Sulfonylureas

(secretagogues) Glinides α-glucosidase

inhibitors

TZDs Insulin GLP-1 agonists

(exenatide, liraglutide) DPP-IV inhibitors

(sitagliptin, saxagliptin) Amylin agonists

(pramlintide)*

*Approved in US only for use in combination with insulin


Liver

Pancreas

Gut

Muscle

HyperglycemiaHyperglycemia

HGO*

Adipose tissue

Glucoseuptake

FFA output

HGO = hepatic glucose output

Glucose absorption

Glucose uptake

Insulin secretion

DeFronzo RA. Diabetes Rev. 1997;5:177-269; Rosenstock J, Wyne K. In: Rosenstock J et al, eds. Textbook of Type 2 Diabetes. 2003:131-154.

Major Organ Systems Contribute Major Organ Systems Contribute to Hyperglycemiato Hyperglycemia

Why Focus on Postprandial Glucose Why Focus on Postprandial Glucose at Levels Close to Goal?at Levels Close to Goal?

0

20

40

60

80

100

Monnier L et al. Diabetes Care. 2003;26:881-885.

<7.3<7.3 7.3-8.47.3-8.4 8.5-9.28.5-9.2 9.3-10.29.3-10.2 >10.2>10.2

HbA1C (%)

Cont

ributi

on to

Ove

rall

Hyp

ergl

ycem

ia (%

)

PPGPPG FPGFPG

The Role of the Incretin System inThe Role of the Incretin System inMaintaining Blood Glucose HomeostasisMaintaining Blood Glucose Homeostasis

Release of GLP-1

and GIPBlood Blood

glucose glucose homeostasishomeostasis

Blood Blood glucose glucose

homeostasishomeostasis

Pancreas

-cells -cells

Glucose Glucose production production

by liverby liver

Glucose Glucose production production

by liverby liver

Glucose Glucose uptake by uptake by

adipose and adipose and muscle tissuemuscle tissue

Glucose Glucose uptake by uptake by

adipose and adipose and muscle tissuemuscle tissue

GI tract

(Glucose dependent)

Glucagon from -cells

Insulin from ß-cells

(Glucose dependent)

Ingestion of food

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

Postprandial Hyperglycemia: The Result of Postprandial Hyperglycemia: The Result of Increased Glucagon and Poor Insulin SecretionIncreased Glucagon and Poor Insulin Secretion

Müller WA et al. N Engl J Med. 1970;283:109-115.

-60 180120 240

Time (min)

120

60

0

Insulin (µU/mL)

100

120

140

Glucagon (pg/mL)

140

80

360

300

240

600

Carbohydrate Meal

Glucose (mg/dL)

Healthy Subjects (n = 14)Type 2 Diabetes (n = 12)

Glucose-Dependent Effects of GLP-1:Glucose-Dependent Effects of GLP-1:Patients With Type 2 DiabetesPatients With Type 2 Diabetes

Nauck MA et al. Diabetologia. 1993;36:741-744.

Minutes

*

*P <0.05

Glucose

(mg/dL)

•*

250250

150

250200

10050

404030302020101000

mIU

/L

15.012.510.0

7.55.0

2002001501501001005050

** * •* * *

**** * * * •*

PlaceboGLP-1

Insu

lin

(pm

ol/L

)G

luco

se

(mm

ol/L

)

0 60 120 180 240

Glu

cago

n (p

mol

/L)

5

20

15

10 * *** *

Effect declines as glucose reaches

normal levels

GLP-1 Actions

Drucker DJ. Diabetes Care. 2003;26:2929-2940; Holst JJ, Ørskov C. Diabetes. 2004;53(suppl 3):S197-S204.

Metabolism of GLP-1Metabolism of GLP-1

DPP-IV = dipeptidyl peptidase-VI

GLP-1GLP-1InactiveInactive

Mixed Meal

GLP-1GLP-1ActiveActive

Plasma

IntestinalRelease of GLP-1

Excreted by kidneys

Rapid inactivation(>80% of pool)

DPP-IVDPP-IV

GLP-1 Actions

Inhibiting DPP-IV Augments GLP-1 LevelsInhibiting DPP-IV Augments GLP-1 Levels

Drucker DJ. Diabetes Care. 2003;26:2929-2940; Holst JJ, Ørskov C. Diabetes. 2004;53(suppl 3):S197-S204.

GLP-1GLP-1InactiveInactive

Mixed Meal

GLP-1GLP-1ActiveActive

Plasma

IntestinalRelease of GLP-1

Excreted by kidneys

Rapid inactivation(>80% of pool)

DPP-IVDPP-IVX

Treatment Strategies That TargetTreatment Strategies That Targetthe Incretin Systemthe Incretin System

GLP-1 AnalogsGLP-1 Analogs DPP-IV InhibitorsDPP-IV Inhibitors

GLP-1 receptor agonist GLP-1 receptor agonist resistant to inactivation resistant to inactivation by DPP-IVby DPP-IV

Highly selective for DPP-IVHighly selective for DPP-IV

Stimulates glucose-Stimulates glucose-dependent insulin secretiondependent insulin secretion

Activity dependent on Activity dependent on incretin actionincretin action

InjectableInjectable OralOral

Longer acting: days to weeksLonger acting: days to weeks Short- vs long-actingShort- vs long-acting



Exenatide Mimics Many Properties of GLP-1Exenatide Mimics Many Properties of GLP-1

GLP-1 Exenatide

Glucose-dependent insulin secretion

Glucagon secretion ( hepatic glucose output) Regulates gastric emptying ( rate of nutrient absorption)

Food intake

Plasma glucose acutely to near-normal levels

Resistant to DPP-IV degradation

Duration in plasma following SC injection Short Long

SC = subcutaneous

GLP-1: LiraglutideGLP-1: Liraglutide

SQ Injectable (0.6 mg, 1.2 mg or 1.8 mg once daily), independent of meals

Balck Box: Risk of Thyroid C-Cell Tumors in rodents. Contraindicatd with FH or personal Hx of medullary thyroid cancer of MEN type 2

No studies combined with insulin Monotherapy

–Dose-related ↓ in HbA1C of 0.98% to 1.45% as monotherapy for 14 wk

–Significantly greater ↓ in HbA1C than glimepiride over 52 wk

Vilbøll T et al. Diabetes Care. 2007;30:1608-1610; Garber A et al. Lancet. 2009;373:473-81; Freeman JS. Available at: http://www.medscape.com/viewarticle/585162.http://www.victoza.com/ Accessed 2010Jan28

GLP-1: LiraglutideGLP-1: Liraglutide

Combination therapy (26 wk): significantly greater ↓ in HbA1C

when added to:–Glimepiride vs rosiglitazone + glimepiride–Metformin + glimepiride vs insulin glargine added to

metformin + glimepiride–Metformin + rosiglitazone vs placebo added to metformin +

rosiglitazone–Metformin, SU, or both vs exenatide added to metformin, SU,

or both Significant decrease in body weight vs placebo or glimepiride Increased risk of hypoglycemia in combination with insulin

secretagogueVilbøll T et al. Diabetes Care. 2007;30:1608-1610; Garber A et al. Lancet. 2009;373:473-81; Freeman JS. Available at: http://www.medscape.com/viewarticle/585162.http://www.victoza.com/ Accessed 2010Jan28

Features of DPP-IV InhibitorsFeatures of DPP-IV InhibitorsSitagliptin & SaxagliptinSitagliptin & Saxagliptin

Antidiabetic effects of DPP-IV inhibitors in animals– Delay in progression from IGT to type 2 diabetes

– Improved glucose tolerance and insulin secretion

– Progressive improvement in glycemic control

– Improved β-cell function

– Increased hepatic and peripheral insulin sensitivity

Indicated as monotherapy or in combination with other oral agents

Once daily oral dosing, independent of meals

Chahal H, Chowdhury TA. Q J Med. 2007;100:671-677; Drucker DJ. Diabetes Care. 2003;26:2929-2940; Nicolucci A, Rossi MC. Acta Biomed. 2008;79:184-191.

Saxagliptin (FDA Approved July 2009)Saxagliptin (FDA Approved July 2009)

Saxagliptin monotherapy (vs placebo in drug-naïve patients)

–Dose-related decreases in HbA1C (0.7% to 1.1%), FPG, and PPG over 12 or 24 wk

–No confirmed hypoglycemic episodes–Headache most common adverse effect (16%)

Joins Sitagliptin as DPP IV agent

How Do Glucose-Lowering How Do Glucose-Lowering Agents Compare?Agents Compare?

Class/Class/DrugDrug

HbAHbA1C1C Reduction (%)Reduction (%) AdvantagesAdvantages DisadvantagesDisadvantages CostCost

MetforminMetformin 1.51.5 • Weight neutralWeight neutral• GI side effectsGI side effects• Contraindicated in renal Contraindicated in renal

insufficiencyinsufficiency$$

SUSU 1.51.5 • Rapidly effectiveRapidly effective• Weight gainWeight gain• HypoglycemiaHypoglycemia

$$

TZDsTZDs 0.5 to 1.40.5 to 1.4• Improved lipid profileImproved lipid profile• Potential Potential in MI in MI

(pioglitazone)(pioglitazone)

• Fluid retentionFluid retention• CHFCHF• Weight gainWeight gain• Bone fracturesBone fractures• Potential Potential in MI in MI

(rosiglitazone)(rosiglitazone)

$$$$$$

αα-glucosidase-glucosidaseinhibitorsinhibitors 1 to 1.51 to 1.5 • Weight neutralWeight neutral

• Frequent GI side effectsFrequent GI side effectsTID dosingTID dosing

$$$$$$


SU = sulfonylureas; GI = gastrointestinal; MI = myocardial infarction; CHF = congestive heart failure

(cont’d)

How Do Glucose-Lowering How Do Glucose-Lowering Agents Compare? Agents Compare? (cont’d)(cont’d)

TID = three times a day

Class/Class/DrugDrug

HbAHbA1C1C Reduction (%)Reduction (%) AdvantagesAdvantages DisadvantagesDisadvantages CostCost

GlinidesGlinides 0.5 to 0.80.5 to 0.8 • Rapidly effectiveRapidly effective• Weight gainWeight gain• TID dosingTID dosing• HypoglycemiaHypoglycemia

$$$$$$

ExenatideExenatide 0.5 to 1.0 0.5 to 1.0 • Weight lossWeight loss

• 2 daily injections2 daily injections• Frequent GI side effectsFrequent GI side effects• Long-term safety not Long-term safety not

establishedestablished

$$$$$$

SitagliptinSitagliptin 0.6 to 0.80.6 to 0.8 • Weight neutralWeight neutral• Long-term safety not Long-term safety not

establishedestablished $$$$$$

InsulinInsulin 1.5 to 3.51.5 to 3.5• No dose limitNo dose limit• Rapidly effectiveRapidly effective• Improved lipid profileImproved lipid profile

• 1 to 4 daily injections1 to 4 daily injections• MonitoringMonitoring• Potential weight gain• Potential hypoglycemiaPotential hypoglycemia

$$$$$$


AACE Guidelines: Patients Naïve to AACE Guidelines: Patients Naïve to Pharmacologic TherapyPharmacologic Therapy

HbAHbA1C1C LevelLevel GuidelineGuideline Pharmacologic OptionsPharmacologic Options

6% to 7%6% to 7%

• Initiate monotherapyInitiate monotherapy• Monitor and titrate for 2-3 moMonitor and titrate for 2-3 mo• Consider combination therapy Consider combination therapy

if goals not met after 2-3 moif goals not met after 2-3 mo

• MetforminMetformin• TZDTZD• SUSU• DPP-IV inhibitorDPP-IV inhibitor• αα-glucosidase inhibitor-glucosidase inhibitor

7% to 8%7% to 8%

• Initiate combination therapyInitiate combination therapy• Rapid-acting or premixed Rapid-acting or premixed

insulin analogs for special insulin analogs for special situationssituations

• All oral medications may be All oral medications may be combined with insulin, based combined with insulin, based on SMBG levelson SMBG levels

• Metformin + SU Metformin + SU oror TZD TZD oror DPP-IV inhibitor DPP-IV inhibitor• SU + TZD SU + TZD oror αα-glucosidase inhibitor-glucosidase inhibitor• DPP-IV inhibitor + TZDDPP-IV inhibitor + TZD• Metformin + SU + TZDMetformin + SU + TZD• Fixed-dose TZD + metformin Fixed-dose TZD + metformin oror glimepiride glimepiride• Fixed-dose metformin + glyburideFixed-dose metformin + glyburide

AACE. Endocr Pract. 2007;13(Suppl 1):4-68.

SMBG = self-monitored blood glucose(cont’d)

AACE Guidelines: Patients Naïve to AACE Guidelines: Patients Naïve to Pharmacologic Therapy Pharmacologic Therapy (cont’d)(cont’d)

HbAHbA1C1C LevelLevel GuidelineGuideline Pharmacologic OptionsPharmacologic Options

8% to 10%8% to 10%• Initiate/intensify combination Initiate/intensify combination

therapy to address fasting and therapy to address fasting and postprandial glucose levelspostprandial glucose levels

• Same as for HbASame as for HbA1c1c levels 7% to 8% levels 7% to 8%

>10%>10%• Initiate/intensify insulin Initiate/intensify insulin

therapytherapy• Rapid-acting + long-acting insulin analogsRapid-acting + long-acting insulin analogs• Premixed insulin analogsPremixed insulin analogs


SMBG = self-monitored blood glucose

In Addition to TLCs, Which Would Be In Addition to TLCs, Which Would Be Appropriate Initial Therapy for Isabel?Appropriate Initial Therapy for Isabel?

Isabel’s treatment plan:– Individualized weight loss and exercise program

– Begin metformin 1000 mg BID

– Self-monitor blood glucose once a day at various times

PreferredPreferred AlternativesAlternatives

• MetforminMetformin• Low-dose SULow-dose SU

• TZDTZD• α-glucosidase inhibitorα-glucosidase inhibitor• Exenatide (monotherapy Exenatide (monotherapy

10/2009)10/2009)• DPP-IV inhibitorDPP-IV inhibitor• GlinidesGlinides• Prandial insulinPrandial insulin


BID = twice a day

Isabel: Two-Year Follow-upIsabel: Two-Year Follow-up

Previous 2 YearsPrevious 2 Years This VisitThis Visit

Lifestyle changeLifestyle change • Walking 30 min 4 x per wkWalking 30 min 4 x per wk• Lost 15 lbLost 15 lb

– Reduced caloriesReduced calories– Reduced fat intakeReduced fat intake

• Walking only 1 or 2 x per wkWalking only 1 or 2 x per wk• Gained back 20 lbGained back 20 lb• Concerned about:Concerned about:

– ““Gaining weight”Gaining weight”– ““Swollen ankles”Swollen ankles”– ““Low blood sugar”Low blood sugar”

MedicationMedication • Metformin 1000 mg BIDMetformin 1000 mg BID • Metformin 1000 mg BIDMetformin 1000 mg BID

SMBGSMBG • Up to 3 times dailyUp to 3 times daily • Once dailyOnce daily

Glucose levelsGlucose levels • HbAHbA1C1C: 6.2%-6.7%: 6.2%-6.7%

• Fasting: 110-130 mg/dLFasting: 110-130 mg/dL• Postprandial: 190-230 mg/dLPostprandial: 190-230 mg/dL• HbAHbA1C1C: 7.8%: 7.8%

AACE Guidelines That Apply to IsabelAACE Guidelines That Apply to Isabel

HbA1C between 7% and 8% Guideline: Initiate combination therapy Two oral-agent options

– Metformin + SU or TZD or DPP-IV inhibitor

– SU + TZD or α-glucosidase inhibitor

– DPP-IV inhibitor + TZD

Triple oral-agent options– Metformin + SU + TZD– Exenatide + SU + metformin

Pramlintide + prandial insulin


– Fixed-dose TZD + metformin or glimepiride

– Fixed-dose metformin + glyburide– Exenatide + SU or metformin or TZD

What Will Influence Treatment What Will Influence Treatment Modification for Isabel?Modification for Isabel?

Class/DrugClass/DrugHbAHbA1C1C

Reduction (%)Reduction (%) HypoglycemiaHypoglycemiaWeightWeightChangeChange

Fluid Fluid RetentionRetention

MetforminMetformin 1.51.5 NoNo NeutralNeutral NoNo

SUSU 1.51.5 YesYes GainGain NoNo

TZDsTZDs 0.5 to 1.40.5 to 1.4 NoNo GainGain YesYes

ExenatideExenatide 0.5 to 1.00.5 to 1.0 NoNo LossLoss NoNo

αα-glucosidase inhibitors-glucosidase inhibitors 0.5 to 0.80.5 to 0.8 NoNo NeutralNeutral NoNo

GlinidesGlinides 1 to 1.51 to 1.5 YesYes GainGain NoNo

PramlintidePramlintide 0.5 to 1.00.5 to 1.0 NoNo LossLoss NoNo

SitagliptinSitagliptin 0.6 to 0.80.6 to 0.8 NoNo NeutralNeutral NoNo

InsulinInsulin 1.5 to 3.51.5 to 3.5 YesYes GainGain NoNo


Which of the Following Anti-Hyperglycemic Which of the Following Anti-Hyperglycemic Agents Address Isabel’s Concerns?Agents Address Isabel’s Concerns?

An α-glucosidase inhibitor, exenatide, or sitagliptin acceptable– Not likely to cause hypoglycemia

– Not likely to induce weight gain

– Not associated with fluid retention

Isabel chose a trial of exenatide based on her concerns about weight gain and hypoglycemia– Initial dosage: 5 mcg SC before breakfast and dinner

– Continue metformin 1000 mg twice a day

– Intensify TLCs

Do you agree with the patient’s decision?We will discuss this during the Q&A

AACE. Endocr Pract. 2007;13(Suppl 1):4-68; Hoogwerf BJ. Curr Drug Ther. 2006;73:477-484.

Exenatide DosingExenatide Dosing

5 mcg SC 0-60 min generally before breakfast and dinner

Titrate up to 10 mcg BID after 1 mo, if no significant nausea or vomiting

Dose of SU may need to be reduced to avoid hypoglycemia

Dose reduction of metformin or TZD not likely

Hoogwerf BJ. Curr Drug Ther. 2006;73:477-484.

Effect of Addition of Exenatide to Oral Effect of Addition of Exenatide to Oral Antidiabetic Agents on Weight: AMIGO TrialsAntidiabetic Agents on Weight: AMIGO Trials

Buse JB et al. Diabetes Care. 2004;27:2628-2635; DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100; Kendall DM et al. Diabetes Care. 2005;28:1083-1091.

AMIGO = AC 2993: Diabetes Management for Improving Glucose Outcomes

Baseline Baseline Weight:Weight: 209.4-218.3 lb209.4-218.3 lb 220.5 lb220.5 lb 213.8-218.3 lb213.8-218.3 lb

*P<0.05; †P<0.001

-2.0-2.0-1.3-1.3

-0.7-0.7

-2.0-2.0

-3.6-3.6†† -3.6-3.6††

-6.2-6.2††

-3.6-3.6** -3.6-3.6††

Sulfonylurea Sulfonylurea (N = 377)(N = 377)

Metformin Metformin (N = 336)(N = 336)

Metformin + Sulfonylurea Metformin + Sulfonylurea (N= 733)(N= 733)

Chan

ge F

rom

Bas

elin

e (lb

)Ch

ange

Fro

m B

asel

ine

(lb)

Exenatide 5 mcg BIDExenatide 5 mcg BID Exenatide 10 mcg BIDExenatide 10 mcg BID PlaceboPlacebo- 8

- 7

- 6

- 5

- 4

- 3

- 2

- 1

0

Proportion of Patients Achieving HbAProportion of Patients Achieving HbA1C1C <7% at 30 Weeks: AMIGO Trials<7% at 30 Weeks: AMIGO Trials

Buse JB et al. Diabetes Care. 2004;27:2628-2635; DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100; Kendall DM et al. Diabetes Care. 2005;28:1083-1091.

Baseline Baseline HbAHbA1C1C:: 8.5%-8.7%8.5%-8.7% 8.2%-8.3%8.2%-8.3% 8.5%8.5%

*P<0.001; †P<0.01; ‡P<0.0001

0

10

20

30

40

50

Chan

ge F

rom

Bas

elin

e (lb

)Ch

ange

Fro

m B

asel

ine

(lb)

Sulfonylurea Sulfonylurea (N = 377)(N = 377)

Metformin Metformin (N = 336)(N = 336)

Metformin + Sulfonylurea Metformin + Sulfonylurea (N= 733)(N= 733)

3333**

991313

99

4646††

2727‡‡

3232††

4141**

3434‡‡

Exenatide 5 mcg BIDExenatide 5 mcg BID Exenatide 10 mcg BIDExenatide 10 mcg BID PlaceboPlacebo

Sitagliptin Added to Metformin Reduces HbASitagliptin Added to Metformin Reduces HbA1C1C in Patients With Inadequate Glycemic Controlin Patients With Inadequate Glycemic Control

0

10

20

30

40

50

7

7.2

7.4

7.6

7.8

8

8.2

Charbonnel B et al. Diabetes Care. 2006;29:2638-2643.

Baseline HbA1C: 7.96% 8.03%

P<0.001

-0.67% -0.67% ((PP<0.001)<0.001)

-0.02%-0.02%

Patients Achieving HbA1C <7% After 24 Weeks

4747

1818

Sitagliptin + Sitagliptin + Metformin Metformin

(n=453)(n=453)

Placebo Placebo (n=224)(n=224)

Perc

enta

ge o

f Pati

ents

Perc

enta

ge o

f Pati

ents

Change in HbA1C After 24 Weeks

00 66 1212 1818 2424

WeekWeek

HbAHbA

1C1C (%

) (%

) Sitagliptin + Sitagliptin + Metformin (n=453)Metformin (n=453)

Placebo (n=224)Placebo (n=224)

Effectiveness of Initial Combination Effectiveness of Initial Combination Therapy With Sitagliptin and MetforminTherapy With Sitagliptin and Metformin

-3.00

-2.50

-2.00

-1.50

-1.00

-0.50

0.00

0.50

1.00

Goldstein BJ et al. Diabetes Care. 2007;30:1979-1987.

Open Label = Patients with baseline HbA1C >11% or FPG >280 mg/dL treated with sitagliptin 50 mg + metformin 1000 mg BID for 24 wk

*P0.001 vs placebo at 24 weeks

Baseline HbA1C: 8.68% 8.87% 8.90% 8.68% 8.79% 8.76% 11.2%

0.170.17

-2.90-2.90

-1.90*-1.90*

-1.40*-1.40*-1.13*-1.13*

-0.82*-0.82*-0.66*-0.66*

Placebo Sitagliptin 100 mg QD

Metformin 500 mg

BID

Metformin 1000 mg

BID

Sitagliptin 50 mg +

Metformin500 mg

BID

Sitagliptin 50 mg +

Metformin1000 mg

BID

Open Label

Chan

ge F

rom

Bas

elin

e (%

)Ch

ange

Fro

m B

asel

ine

(%)

Adverse-Event Profiles of Exenatide Adverse-Event Profiles of Exenatide and Sitagliptinand Sitagliptin

ExenatideExenatide SitagliptinSitagliptin5 mcg BID5 mcg BID 10 mcg BID10 mcg BID 100 mg/day100 mg/day

HypoglycemiaHypoglycemiaWith metforminWith metforminWith SUWith SUWith metformin + SUWith metformin + SU

4.5%4.5%14.4%14.4%19.2%19.2%

5.3%5.3%35.7%35.7%27.8%27.8%

1.2%1.2%

NasopharyngitisNasopharyngitis 5.2%5.2%

URTIURTI 6.3%6.3%

HeadacheHeadache 9%9% 5.1%5.1%

DizzinessDizziness 9%9%

Abdominal painAbdominal pain 2.3%2.3%

NauseaNausea 44%44% 1.4%1.4%

VomitingVomiting 13%13%

DiarrheaDiarrhea 13%13% 3.0%3.0%

DyspepsiaDyspepsia 6%6%

Byetta® (exenatide injection) prescribing information; Januvia (sitagliptin tablets) prescribing information.

URTI = upper respiratory tract infection

Isabel: Follow-up on Combination TherapyIsabel: Follow-up on Combination Therapy

1 month– Had lost 3 lb

– FBG: 110-130 mg/dL

– PPG: 160-190 mg/dL

3 months– Patient pleased with weight loss (now a total of 6 to 7 lb)

– FBG: 105-115 mg/dL

– PPG: 130-160 mg/dL

– HbA1C: 6.9%

Improved glycemic control + weight loss = reduced risk for macrovascular/microvascular complications

SummarySummary

Type 2 diabetes affects nearly 8 million Americans

Early and intensive treatment to lower HbA1C reduces risk for macrovascular and microvascular complications

Postprandial hyperglycemia should be a focus of diabetes management

GLP-1 analogs and DPP-IV inhibitors– Maintain normal blood glucose by regulating postprandial

glucose

– Are recommended as combination therapy with other OADs

– Induce weight loss or weight neutral

– Significantly reduce HbA1C vs metformin or SU monotherapy

Summary Summary (cont’d)(cont’d)

Exenatide (GLP-1 analog)– Twice-daily injectable

– Risk for hypoglycemia with SU

Sitagliptin & Saxagliptin (DPP-IV inhibitor)– Once-daily oral

– Risk for hypoglycemia with SU

New agents in development with less frequent dosing Addition of GLP-1 analog or DPP-IV inhibitor

– Can help reduce HbA1C to recommended target

– May contribute to weight loss

– Together, risk for diabetes-related complications may be reduced

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