PowerPoint-Pr

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The changing picture of Type 2 diabetes
E. Standl
International Diabetes Research Institute Munich
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Case report Mr. K., 56 Yrs
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Case report Mr. K., 56 Yrs

• First visit Dyslipidemia
• Triglycerides 786 mg/dl
• Total Cholesterol 318 mg/dl
• LDL-Chol not measurable
• HDL-Chol 26 mg/dl
• Preprandial BG 178 mg/dl
• HbA1c 8.8
• Blood pressure 168/92 mmHg

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Case report Mr. K., 56 Yrs

• Diagnoses
• Metabolic Syndrome
• Type 2 Diabetes mellitus
• Obesity
• Hypertension
• Dyslipidemia
• Coronary heart disease
• Indication for a potentially
  fatal constellation

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Pathogenetic key organs and hormones in Type 2
diabetes
Seeley et al, Nature Medicine (2004) 10 454
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Metabolic syndrome / Insulin resistance causes
and associated disease
INSULIN RESISTANCE METABOLIC SYNDROME
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IRIS II Insulin Resistance and Chemical Profile
Pfützner/Standl Diabetic Medicine 2004
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Campaign Enduring Freedom from complications
in Type 2 diabetes
Below 6,5 and 3x below 100! i.e. below 6,5
HbA1c below 100 mg/dl fasting blood
glucose below 100 mg/dl LDL-Cholesterol
below 100 mmHg mean blood pressure
(eg. below 120/80)
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Percentage of patients achieving set
intensive targets in the Steno 2 Study
HbA1clt6,5
Cholesterollt175mg/dl
Triglycerideslt150mg/dl
Syst BPlt130mm Hg
Diast BPlt80mm Hg
20
40
60
80
100
0
of Patients
Gaede et al. NEJM(2003) 348383-393
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Despite major advances in the treatment of Type 2
diabetes, only a minority of patients meets
glycemic targets longer term
because

• efficacy of present pharmacotherapy options
• is limited
• insulin secretory deficit increases progressively
• pathophysiology is only partially understood
• present pharmacotherapy may be burdened by
• side effects
• self management by the patient is mandatory, but
• often a difficult challenge

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All Current Treatments for Type 2 Diabetes Have
Limitations
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Arguments in favor of early combination therapy

• additive efficacy through different mode of
  actions
• therapy of different abnormalities
• at medium dose 70-80 of maximum effect ? less
• side effects

a-Glucosidase inhibitors
Incretin enhancers
Sulfonylureas und Analogs
Glitazones
Metformin
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Target-driven approach for sustained glycaemic
control
Monotherapy
Insulin /- oral agents
Campbell IW. Br J Cardiol 20007625-31
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Current Oral Therapies Do Not Address the
Multiple Defects in Type 2 Diabetes
Impaired insulinaction
Inadequate glucagonsuppression (?-cell
dysfunction)
Glucoseinflux from GI1 tract
Chronicß-celldecline
Acuteß-celldysfunction
Sulfonylureas
a-Glucosidaseinhibitors
TZDs2
unmet need
unmet need
Metformin
Glinides
? Plasma glucose and disease progression
1 Gastrointestinal 2 Thiazolidinedione Adapted
from DeFronzo RA. Br J Diabetes Vasc Dis.
20033(suppl 1)S24S40
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ß-Cell Mass Is Significantly Decreased in Obese
IFG and T2DM Patients
P lt .05 vs NGTP lt .001 vs NGT Adapted from
Butler A, et al. Diabetes. 200352102-110.
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Association of waist to hip ratio with parameters
of metabolic syndrome
HDL cholesterol (mmol/l)
2h triglyceride (mmol/l)
2h insulin (mmol/l)
Median systolic blood pressure (mmHg)
Diabetes prevalance ()
Mc Keigne et al, Lancet (1991) 337 382
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IDF consensus definition (2005)
For country/ethnic specific waist circumference
values, see Alberti KGMM., IDF Consensus on the
Metabolic Syndrome Definition and Treatment,
presented at 1st International Congress on
Prediabetes and the Metabolic Syndrome, Berlin,
14 April 2005, available on-line
http//www.idf.org/webcast
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Interrelation of adipose tissue, islet
health, and glucose tolerance state
OBESITY
INSULIN RESISTANCE
healthy islets
impaired islets
normal glucose tolerance
impaired glucose tolerance
Diagram courtesy of E. Standl, Munich
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Rimonabant Phase III program
Seven studies including gt 13,000 patients
RIO Program in Obesity(gt6,600 patients enrolled)
RIO-North America - 2-year treatmentRIO-Europe -
2-year treatmentRIO-Lipids - 1-year
treatmentRIO-Diabetes - 1-year treatment
STRATUS Program in Smoking Cessation (gt6,500
patients enrolled)
STRATUS US - 10-week treatmentSTRATUS Europe -
10-week treatmentSTRATUS worldwide - 1-year
treatment
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Changes in Weight and Waist Circumference
Weight (kg)
Completers
Weight change (kg)
-3.6
-4.8
-8.6
Weeks
ITT LOCF placebo -1.8kg 5 mg
-3.4kg (p 0.002 vs. placebo) 20 mg
-6.6kg ( p lt 0.001 vs. placebo)
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Mechanism of action of GLP-1-analogs and
incretin enhancers (e.g. the DPP IV inhibitor
vildagliptin)
GLP-1

• stimulates glucose dependent insulin secretion
• inhibits glucagon secretion
• delays gastric emptying
• has a potential of ß-cell regeneration and
  inhibits apoptosis
• of pancreatic ß-cell
• has to be injected

Incretin enhancers

• Inhibit GLP 1 inactivation (via DPP IV
  inhibition)
• are effective as oral drugs

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Exenatide and glycemic control added
to combination therapy with Metformin and a
Sulfonylurea in Type 2 Diabetes
Kendall et al, Diabetes Care 28 (2005) 1083-91
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GLP-1 breakdown by DPP IV
Holst, Diabetologia 48(2005) 612-15
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Mean Efficacy of Pharmacotherapeutic
Options in Type 2 Diabetes
Mean HbA
-
Lowering
1c
Drug Option
Capacity ()
0,7
CB1 Blocker
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Prandial insulin approach in type 2 diabetes
Mealtime
glucose
spikes
Fasting
hyperglycaemia
Normal
Time (hours)
modified from Riddle MC.Diabetes Care
199013676-686
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Type 2 Diabetes disordered post-meal suppression
of endogenous glucose production
15
Human insulinLispro
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Endogenous Glucose Production µmol/kg/min
5
0

N 8, T2DM 0.075 U/kg sc
plt0,05


-5

-10
-40
0
40
80
120
200
160
240 min
Bruttomesso et al. Diabetes 1999 48 99
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Targeting postprandial hyper- glycemia with rapid
acting insulin analogs (vs. regular insulin)

• more physiological insulin supplementation
• potential to improve glucose control further
• no snacks inbetween and after meals necessary
• potential for easier weight regulation
• potential for less hypoglycemia
• quality of life improvement (flexibility of
  meals,
• no precalculation of meals, no lag phase
  between
• insulin injection and meal)
• no longterm head to head comparison to regular
• insulin for outcomes

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Airway Delivery ofInhaled Insulin
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Various Inhalation Systems For Insulin
Pfizer
/
Aventis
/Nektar
Aradigm
/Novo
Nordisk
KOS
Mannkind
Aerogen
Lilly/
Alkermes
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Bronchiale und alveoläre Resorptionsfläche
Bronchialsystem
Alveolen
Alveolen
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Pharmacodynamics of Exubera
12
10
Lispro
Regular insulin
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Inhaled insulin
6
GIR - baseline mg/kg/min
4
18 U Lispro
18 U Regular
2
6 mg Inhaled
time (h)
0
0
1
2
3
4
5
6
7
8
9
10
Adopted from Heise T. et al. ADA 2000
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Overview Phase 3 program
Phase 3 Studies (106, 107, 108, 109, 110)
Equivalence (106, 107, 108)
Superiority (109, 110)
3 months
6 months
Type 1 (106, 107)
Type 2 (109, 110)
Type 2 (108)
Failing OAs
Insulin Treated
Failing Diet/Exercise
SC Insulin vs. Exubera
TZD vs. Exubera
OA vs. OA Exubera
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Inhaled insulin dosing in mg
1 mg approximately 2.75 I.U. 3 mg approximately
8.0 I.U.
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Insulin pretreated type 2 diabetes
10
Inhaled insulin (n143) SC insulin (n145)
9
8
Mean HbA1c ()
7
6
0
Screening
Baseline 6 12
18 24 Week 24

(LOCF)
Duration of treatment (weeks)
Hollander et al. Diabetes Care (2004)272356
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Potential downsides of inhaled insulin

• Hypoglycemia (/-)
• Body weight (/-)
• Cough (25 vs 5)
• Lung Function (some changes statistically
• significant, but
  clinically not
• relevant)
• Approved only in non smokers (!)
• Insulin antibody formation(Igg, binding in
• T1D 29 vs 3, T2D 10
  x lower)
• Longterm safety (?)

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Conclusion
Inhaled insulin may be used as short
acting regular insulin (gtT2 vs T1 ) and
administered shortly prior to meals. Longterm
safety needs to be monitored further by good
longterm post-marketing surveillance.
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Emerging therapies do they bring advances for
better management of type 2 diabetes?
Better?

• efficacy of pharmacotherapy options?
• preservation of beta-cell function?
• understanding of pathophysiology?
• Side effect profile?
• self management by the patient?
• longterm outcome?

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IRIS-Study (representative cohort of 4575 type 2
diabetic patients in Germany) Proportion of
patients achieving specific HbA1c targets
of Patienten
61
48
18
32
lt6.5 lt7.0
lt7.5 lt8.0
HbA1c target
Rihl, Biermann, Standl Diabetes Stoffw.
(2002)11150-158
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Relative contribution of postprandial vs fasting
blood glucose to glycemia as assessed by
quintiles of HbA1c
postprandial blood glucose fasting blood glucose
contribution ()
HbA1c quintiles ()
(Monnier et al., 2003)
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Policy of selecting the appropriate antidiabetic
therapy according to the metabolic situation
Postprandial hyperglycaemia
alpha-glucosidase inhibitor, short acting
sulphonylurea, Glinide, short acting
regular insulin or insulin analog, respectively
Fasting hyperglycaemia
biguanide, long acting sulphonylurea,
glitazone, long acting insulin or insulin
analog, respectively
Insulin resistance
biguanide, glitazone, alpha-glucosidase inhibitor
Insulin deficiency
sulphonylurea, glinide, Insulin
Standl et al, Diabetologia (2003) 46 Suppl 130-36