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Diabetes U

Brian LaEndocrinology, DiabGessler C

Winter HaveOffice: 863

Email: brian.lake

May 2

pdate 2012

ke, D.O.

tes, and Metabolismlinic, P.A.

, FL 33881 -294-0670

gesslerclinic.com

2012

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Financial

Speakers bureau for:

Byetta / Bydureon Lantus and Apidr

Tradjenta (Boerin

Synthroid (Abbott

isclosures

(Amylin)(Sanofi Aventis)

er Ingelheim / Lilly)

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Obje

Discuss the epidemiol

Discuss the pathogeneprogressive disease

,glycemic goals

Examine the AACE alg

treatment Review newer diabet

patients achieve goals

tives

gy of type 2 diabetes

sis of diabetes as a

,

orithm for diabetes

s medications to help

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What is the scop of the problem?

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Facts onFacts on

Of 311 million Americans, 26 mil

An estimated 79 million America

A condition that increases thdisease and stroke

Diabetes more likely to affect ol

2010

Diabetes affects 8.3% of all Am20 and older

Some 27% of people with dinot know they have the dis

DiabetesDiabetes

lion Americans have diabetes

n adults have pre diabetes

ir risk of type 2 diabetes, heart

er Americans

ricans and 11.3% of adults age

betes 7 million Americans doease

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Estimated percentage oor older with diagnos

diabetes, by age group,20

3.7%

.

20-44 45-64

Age Grou

Source: 20052008 National Health and Nutrition Exa

26.9%

people aged 20 yearsd and undiagnosed

United States, 20058

65

ination Survey.

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1,052,00

Estimated number of ndiabetes among people a

age group, Unit

465,000

20-44 45-64

Age Gro

Source: 20072009 National Health Interview Survey

0

w cases of diagnosedged 20 years or older, byed States, 2010

390,000

65

p

estimates projected to the year 2010.

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Diabetes Epidemiology 1956-2009

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Age-adjusted percentage of adults age

2007

MMWR 58:1259-1263, 2009

d 20 years with diagnosed diabetes,

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Age-adjusted percentage of adults2007

MMWR 58:1259-1263, 2009

aged 20 years who are obese,

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40

50

60

nt

Total

Non-Hispanic Black

Estimated lifetime risk o

individuals born in the

0

10

20

30

Men

Perc

e

Narayan et al, JAMA, 2003

on-Hispanic White

ispanic

developing diabetes for

United States in 2000

Women

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The Big Picture 177 million worldwide

4th leading cause of d India 33 million peopl

Population of diabete

2025

One out of every threwill develop diabetes

Time magazine Dece

ith Type 2 DM

eath by disease with diabetes

wwill double to triple by

Americans born today

ber 2003; CDC

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So what have we lfew decades to hel

arned over the lastattack to problem?

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Diabetes is a pro

Two basic underlying

2 diabetes: Insulin resistance

Im aired insulin secreti

pancreas

gressive disease

echanisms lead to type

n from beta cells within the

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Diabetes is a pro

Up to 70-80% of beta c

time of diagnosis of typ Generally, alterations i

been present for 5+ ye

diagnosis of type 2 dia Newer therapies are be

mechanisms of preservcell function and alterin

1. DeFronzo RA. From the triumvirate to the otreatment of type 2 diabetes mellitus [Banting

gressive disease

ll function is lost at the

2 diabetes1

glucose handling havers prior to the laboratory

etes ing targeted at

ing and improving betainsulin resistance

minous octet: a new paradigm for theLecture]. Diabetes. 2009: 58: 773-795.

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-Cell mass in

2.0

2.5

3.0

3.5

e(%)

-50%-50%

0.0

0.5

1.0

1.5

ND IFG

b-Cellvolu

Obese

Butler et al. Diabetes. 2003

ND=non-diabetic; IFG=impaired fasting glucose; T2DM

ype 2 diabetes

2DM ND T2DM

Lean Type 2 diabetes mellitus

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The New

DeFronzo RA. From the triumvirate to the omtreatment of type 2 diabetes mellitus [Banting

Paradigm

inous octet: a new paradigm for theLecture]. Diabetes. 2009: 58: 773-795.

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Knowing the scopeare we doing co

of the problem, howtrolling patients?

P t f P ti t With Di b t

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Percentage of PatiHaving

80

100

US Adults With Diagno

NHA

73

Percentat goal

Harris MI, et al. Diabetes Care. 1999;22:403-408.

0

20

40

Diet alone Oral age

38

Therapy u

nts With Diabetes 1C

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80

90

100

en

IRIS-Study (representative cohoin Germany): Proportion of patient

0

10

20

30

40

50

60

18 32

%o

fPatient

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16%

Percentage of adultsreceiving treatm

medication, Unit

58%

Insulin only Insulin and oral medicatio

Source: 20072009 National Health Interview Surve

12%

with diagnosed diabetesnt with insulin or oral

d States, 20072009

Oral medication only No medication

.

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What about the neminimal cardiova

i.e. ACCORD, A

er studies showingcular benefit with

VANCE, VADT

R l ti Ri k f i f

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Relative Risk ofDiabetic Complic

11

13

15

K

DCCT Research

1

3

5

7

6 7 8 9

RELATIVER

I

Mean A1C

rogression oftions - DCCT

Retinop

roup, N Engl J Med 1993, 329:977-986.

10 11 12

Neph

Neurop

Lifetime Be

nefits of

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Lifetime BeIntensive Ther

Gain of 15.3 years of cocompared to convention

.

conventional therapy

DCCT Study

nefits of py (DCCT)

plication free livingl therapy

Group,JAMA 1996, 276:1409-1415.

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DCCT

10% reduction in HbA1

43% reduced risk of re

ncrease r s owith coma and/or seiz

DCCT Research

c

inopathy progression

evere ypog ycem are

roup, N Engl J Med 1993, 329:977-986.

L i A1CL i A1C d Ri kd Ri k

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Lowering A1CLowering A1Cof Complicatioof Complicatio

(%)* 0

-10-12

United Kingdom ProsUnited Kingdom Pros(UK(UK

*Percent risk reduction per 0.9% decrease in HbA1C;

UKPDS. Lancet. 1998;352:837-853.

Reductioninris

=0.029

p=0.0099

p=0.052

p=0.015

p=0.0

-20

-30

-40

-50

-25

-3

-21

educes Riskeduces Riskss

Any diabetes-related endpoint

ective Diabetes Studyective Diabetes StudyDS)DS)

00054

endpoint

MI

Retinopathy

Albuminuria at 12years

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Current recommendations addressmacrovascular disease with strict g

ADA position statement2010 Standards of Care

guideline

ack of evidence of reduction inycemic control

ADA Standards of Care. DiabetesCare 2010;33

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6.4% vs. 7.5%

Sklyer JS, et al. Intentive glycemic control and the prevention of caDiabetes Care 2009;32:187-92.

More advanced disease, in general, with av11 years.

6.3% vs. 7.0% 6.9% vs. 8.5%

rdiovascular events. A position statement of the ADA/ACC/AHA.

erage time from diagnosis of DM2 of 8-

ACCORD tudy 2008

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ACCORD tudy - 2008

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ACCORD s

Halted after 3.5 years

54 additional deaths in203)

requiring assistance

Increased weight gain

We remain unsure of rdeath rate (possibly mreduction, hypoglycem

ACCORD Study Group. Effects of Intensive2008; NEJM 2008 Jun 12; 358(24): 2545-59.

tudy - 2008

intensive group (257 vs.

,

in intensive group

asons for increasedgnitude or speed of A1c

ia, adverse rxns, etc)

lucose Lowering in Type 2 Diabetes. NEJM

ADVANCE

t d 2008

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ADVANCE

Summary most patienand metformin

Intensive glucose contr 10% reduction in com

macrovascular event re uc on n m c

21% reduction in nep No significant effects No significant effects

cardiovascular mortality Consistent treatment

subgroups

ADVANCE Collaborative Group. IntensivOutcomes in Patients with Type 2 Diabete

study - 2008

s on gliclazide MR (SU)

l resulted in:bined, major micro- or

ovascu ar even sropathy

on macrovascular events on all-cause or

effects in patient

Blood Glucose Control and Vasculars. NEJM 2008; 358(24):2560-2572.

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VADT

No statistically significcardiovascular events

No statistically significmicrovascular events

Increased risk of hypogroup (link found with

Rosiglitazone used in72% of standard groufound with CV events

Glucose Control and Vascular Complications2008 Dec 17.

-2008

nt effect onr death

nt effects on

lycemia in intensiveV events)

5% of intensive andand no associationr death

in Veterans with Type 2 Diabetes. NEJM.

f f f

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Three large trials of glycemic controlCVD benefit

Sklyer JS, et al. Intentive glycemic control and the prevethe ADA/ACC/AHA. Diabetes Care 2009;32:187-92.

published in 2008 failed to find

tion of cardiovascular events. A position statement of

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ADA Standards of Care. Diabetes CareJanuary 2012;35: Supplement 1

2012 ADA guideline appropriatelydiscusses microvascular benefits of

A1C < 7% while acknowledginglack of proven macrovascularbenefits at the A1C values that werestudied.

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2. Lipid recommendations in t

diabetes

ADA St

pe 2

ndards of Care; Diabetes Care, January 2011

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Conclusion: The combination of fenofibrate of fatal cardiovascular events, non-f

with simvastatin alone.

April 29, 2010 NEJM

ate and simvatatin did not reduce thetal MI or non-fatal stroke, as compared

ACCORD BP: Results

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ACCORD BP: Results

Conclusions: In patients with type 2cardiovascular events, targeting a sysmmHg, as compared with less than 1

fatal and nonfatal major CVD events.

iabetes at high risk fortolic blood pressure of less than 1200 mmHg, did not reduce the rate of

Conclusions:

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Conclusions:

New clinical trial data has solidified cu A1C ~ 7% SBP ~ 130 mmHg LDLc < 100mg with statin (ACCOR

Use of ASA in higher risk patients wit

reduction: A1C < 7% SBP < 130 (ACCORD achieved 119 Addition of fibrate or niacin to statin t ASA should not be used if CVD risk

rent treatment goals:

lipid achieved 80 mg/dL)

h diabetes

mHg SBP)

o target TG if LDLc already at goal

s low

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Now that we k

recommendationdoing globally, wha

us get our pa

ow the newer

, and how we areis available to help

ents to goa

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Standards of Medi

Sta

Dia

doi:

Publ

chadiab

al Care in Diabetes

dards of Medical Care in Diabetes 2012

etes Care January 2012 35:S11-S63;

0.2337/dc12-s011

ished yearly by the ADA in Diabetes Care

ges in standard of care for patients withetes

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AACE/ACE DiabGlycemi

A1c based algonewer therapies a

in medications uba

tes Algorithm forControl

ithm addressingllowing for flexibility

ilized. Evidenceed.

AACE/ACE Diab

tes Algorithm for

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AACE/ACE Diab

Glycemi Permission granted for

algorithm from the AmClinical Endocrinologis

Algorithm available at:

https://www.aace.com/iccontrolalgorithmppt.p

Accessed 4/17/12

tes Algorithm for

Control electronic use of

rican Association ofts.

sites/degault/files/glycemdf

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What do we now h

to glycemic goals,and help reduce ris

comp

ve to bring patients

void hypoglycemia,of MICROvascular

at ons

Therapeuti Options for

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Therapeuti

Type1995

Sulfonylureas

INSULIN

Regular

Ultralente

Options for

2 DM2012

Sulfonylureas

INSULIN

NPH

Meglitinides

Incretin mimetics

Amylinanalogues

egu ar

Insulin analogues

Peak-less basalinsulins

Metformin

TZDs

Alpha glucosidaseinhibitors

n tors

Bile Acid bindingsequestrants

Bromocriptine

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DeFronzo RA. From the triumvirate to the omtreatment of type 2 diabetes mellitus [Banting

inous octet: a new paradigm for theLecture]. Diabetes. 2009: 58: 773-795.

N t i

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Newer t

There is no one perfeceight currently acceptehandling

Targeting glycemic go

earlier in the disease preductions in risk

Most newer therapies

hypoglycemia and restsecretion

erapies

medication to attack alld defects in glycemic

ls more aggressively

rocess has durable

re aimed at reducing

oring endogenous insulin

Current Oral Therapies DoDefects in Type 2 Diabetes

ot Address the Multiple

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Defects in Type 2 Diabetes

Impairedinsulinaction

Inadegluc

suppr(-

dysfu

Glucoseinflux from

GI1 tract

-Glucosidase TZDs2 unme

48

1 Gastrointestinal

2 ThiazolidinedioneAdapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003;3(

n tors

Metformin

Plasma glucose an

Sulfonylureas

uategonssionellction)

Chronic-cell

decline

Acute-cell

dysfunction

t need unmet need

uppl 1):S24S40

Glinides

disease progression

Incretin effect onIncretin effect on insulin secretion insulin secretion

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sulin(mU

/l)

80

60

40Incretin

effect

Control subjects (n=8)

Nauck et al. Diabetologia. 1986

Oral glucose loadIntravenous glucose infusion

Time (min)

I

20

0

18060 1200

sulin(mU

/l)

80

60

40

People with Type 2 diabetes (n=14)

Time (min)

I

20

0

18060 1200

GLP-1: effe ts in humans

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After food ingestion

GLP-1 is secreted from

L-cells of the jejunumand ileum

That in turn

Drucker. Curr Pharm Des. 2001Drucker. Mol Endocrinol. 2003

Stimulates glucose-dependent insulin secretion

Suppresses glucagonsecretion

Slows gastric emptying

Long-term effectsin animal models:

Increase of -cell massand improved -cell function

Improves insulin sensitivity

food intake

GLPGLP--1 preserves h1 preserves h man islet morphologyman islet morphology

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Control

and function in cand function in c

Farilla et al. Endocrinology. 2003

Day 1

+ GLP-1

ltured islets in vitro ltured islets in vitro

Day 3

Day 5

GLP 1 rece tor agonists

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GLP-1 rece

Exenatide, Liraglutide

Injectable medications tsupraphysiologic levelsexert their effects

, ,

Generally targets post-but exerts effects on fast

Hypoglycemia is rare wi

sulfonylureas or insulinCan perpetuate a weig

Average of approximatreduction

tor agonists

hat allowf exogenous GLP-1 to

randial glucose levelsing glucose as well

thout concurrent use of

t benefit

ly a 1.5% HbA1c

GLP 1 receptor a onists (negatives)

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GLP-1 receptor a

Cost

Potential for nauseaCases of pancreatitis rehemorrha ic and necroti

C-cell hyperplasia seenblack box warnings for(with extended release p

relevance in humans

onists (negatives)

ported (includingin

in animal models withedullary thyroid cancerreparations). Unsure of

GLP 1 athway

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GLP-1

Endogenous GLP-1 isdipeptidyl peptidase-4 (matter of minutes

DPP-4 enzyme inhibitio

GLP-1 concentrations sttime in circulation allowi

athway

rimarily degraded by thePP-4) enzyme within a

keeps endogenous

ble for longer periods ofg it to exert its effects

Inhibition of DPP 4 Inc

reases Active GLP 1

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Inhibition of DPP-4 Inc

Intestinal

GLP-1release

Meal

Intestinal

GLP-1release

Meal

c ve

GLP-1

DPinhi

c ve

GLP-1

DPinhi

Adapted from Rothenberg P, et al. Diabetes. 2000;4

reases Active GLP-1

GLP-1inactive

P-4itor

DPP-4

GLP-1inactive

P-4itor

DPP-4

(suppl 1):A39.

DPP-4 i

hibitors

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DPP-4 i

Sitagliptin, Saxagliptin, Lin

Decrease the rapid degrad

to allow it to exert its effectsGenerally targets post-pran

Generally a very tolerablepotential side effects

Hypoglycemia rare without

sulfonylureas or insulinWeight neutral

hibitors

gliptin

tion of endogenous GLP-1

longerdial glucose values with a

rug class with minimal

concurrent use of

DPP-4 Inhibit r (negatives)

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DPP-4 Inhibit

Cost

Cases of pancreatitis rehemorrhagic and necroti

Small HbA1c lowerin

r (negatives)

ported (includinging)

ower ~0.5%

DPP-4 therap ideal patient

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DPP 4 therap

Patients with renal dysfmetformin as first line th

In combination with metinto the diagnosis of dia

Patients with multiple cavoid hypoglycemia

Patients with post-pran

(potentially as a substitu

ideal patient

nction or intolerant ofrapy

formin, particularly earlyetes

morbidities wishing to

ial hyperglycemia

e of a sulfolylurea)

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Other Topics in the News

Pioglitazone and

Bladder Cancer

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Pioglitazone and

6/15/11 The FDA isspublic to inform them of

of increased risk of blawho took pioglitazone f

Increased risk based o

27.5 excess cases of bl

100,000 person-years fnever use of pioglitazo

1. Lewis JD, Ferrara A, PengHedderson M, Bilker WB, Quesenber

2. SDI, Vector One: Total Patient Tracker (TPT). January 2010-O

Bladder Cancer

ed a statement to thea possible association

der cancer in patientsr >1 year (based on 5-yr

dose and duration

adder cancer per

llow-up, compared toe

yJr, et al. Diabetes Care. 2011;34:916-22.

tober 2010. Data extracted 12-15-10.

Pioglitazone and

Bladder Cancer

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Pioglitazone and

Also, epidemiologic stusimilar association of bl

pioglitazone with incre

FDA guidance is to not

patients with active blawith caution in patientscancer

1. US Food and Drug Administration. http://www.fda.gov

Bladder Cancer

y in France showingadder cancer with

sing dose and duration

use pioglitazone in

der cancer and to usewith a history of bladder

Drugs/DrugSafety/ucm259150.htm

Sum ary

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Sum

Diabetes is an epidemino signs of slowing

AACE and ADA algorittoward achieving contr

complications in our di A goal HbA1c of < 7%

reduce diabetic microv

ary

problem that is showing

ms can help guide usl and preventing

betic patients emains a realistic goal to

scular complications

Sum ary

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Sum

With ACCORD, VADT,showing minimal cardio

intensive glycemic contadvanced disease, we

Goals and therapies shdiscussed with patients

evolve in our knowledgof diabetes

ary

and ADVANCE trialsvascular benefit of

rol on patients withhould be cautious in this

uld continue to beas we continue to

of the care and control

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Questi ns???