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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???