presentation eberhard standl changing picture type 2 warsaw 2006

Metabolic syndrome / Insulin resistance:causes and associated disease... Despite major advances in the treatmentof Type 2 diabetes, only a minority of patients meets glycemic targets lo

The changing picture

of Type 2 diabetes

E Standl

International Diabetes Research Institute

Munich

Case report – Mr K., 56 Yrs

Case report – Mr K., 56 Yrs

Case report – Mr K., 56 Yrs

• Coronary heart disease

Indication for a potentially

fatal constellation

Pathogenetic key organs and hormones

Adipose tissue

Leptin &

Adiponectin

Glucagon

Metabolic syndrome / Insulin resistance:

causes and associated disease

IRIS II: Insulin Resistance and

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)

Despite major advances in the treatment

of Type 2 diabetes, only a minority of

patients meets glycemic targets longer term

1) efficacy of present pharmacotherapy options

is limited 2) insulin secretory deficit increases progressively 3) pathophysiology is only partially understood 4) present pharmacotherapy may be burdened by side effects

5) self management by the patient is mandatory, but often a difficult challenge

because

All Current Treatments for Type 2 Diabetes

Have Limitations

ureas

Sulfonyl-Insulin Metformin Acarbose

Achieving goals with

• therapy of different abnormalities

• at medium dose 70-80% of maximum

effect  less

side effects

Glitazones

α-Glucosidase inhibitors

Metformin

Sulfonylureas

und Analogs

Incretin enhancers

+Monotherapy Insulin +/- oral agents

Campbell IW Br J Cardiol 2000;7:625-31

Target-driven approach for sustained

ULN

Diagnosis +5 yrs +10 yrs + 15 years

Failure-based treatment

of symptoms approach

1 Gastrointestinal

2 Thiazolidinedione

Adapted from DeFronzo RA Br J Diabetes Vasc Dis 2003;3(suppl 1):S24–S40

Current Oral Therapies Do Not Address the

Multiple Defects in Type 2 Diabetes

Sulfonylureas Glinides

Impaired insulin action

Inadequate glucagon suppression (-cell dysfunction)

Acute β-cell dysfunction

β-Cell Mass Is Significantly Decreased in Obese IFG and

Mc Keigne et al, Lancet (1991) 337: 382

IDF consensus definition (2005)*

Central Obesity

Waist circumference – ethnicity specific*

– for Europids: Male ≥ 94 cm Female ≥ 80 cm

plus any two of the following:

Raised Triglycerides ≥150mg/dL (1.7mmol/L)

or specific treatment for this lipid abnormality

Low HDL Cholesterol <40mg/dL (1.03 mmol/L) in males

<50mg/dL (1.29 mmol/L) in females

or specific treatment for this lipid abnormality

Raised blood pressure Systolic : ≥130 mmHg or

Diastolic: ≥85 mmHg or

Treatment of previously diagnosed hypertension

Raised fasting plasma glucose

(FPG)

FPF ≥100 mg/dL (5.6 mmol/L)

or Previously diagnosed type 2 diabetes

If above 5.6 mmol/L or 100 mg/dL, OGTT is strongly recommended but is not necessary to define presence of the syndrome.

* 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

Interrelation of adipose tissue,

islet health, and glucose tolerance state

INSULIN RESISTANCE

+ healthy islets + impaired islets

normal glucose tolerance

impaired glucose tolerance

OBESITY

Diagram courtesy of E Standl, Munich

Metabolic peripheral effects

FFA cle ara

nce

FFA cle ara

nce

Rimonabant (CB1 Blocker): A Multi-Impact Drug



Hyperinsulinemia Insulin sensitivity restored

 TG

 HDL-C

Control of nicotine dependence

Decrease in food intake (palatable and non-

palatable food)

Van Gaal et al; Lancet (2005) 365: 1389-97

The Endocannabinoid System

Rimonabant Phase III program

Seven studies including > 13,000 patients

RIO Program in Obesity

(>6,600 patients enrolled)

(>6,500 patients enrolled)

Placebo Rimonabant 5mg Rimonabant 20mg

Changes in Weight and Waist Circumference

n=315 n=330

n=317

7.3 0.8 7.3 0.8

7.2 0.9 Baseline

6.7 0.9 7.2 1.1

7.3 1.1 Year 1

-0.7 (0.1)** -0.2 (0.1)*

Difference

rimonabant

v placebo (SEM)

-0.6 0.8 -0.1 1.0

0.1 1.0 Change

Rimonabant

20 mg

Rimonabant

5 mg Placebo

%

7.3 0.8 7.3 0.8

7.2 0.9 Baseline

6.7 0.9 7.2 1.1

7.3 1.1 Year 1

-0.7 (0.1)** -0.2 (0.1)*

Difference

rimonabant

v placebo (SEM)

-0.6 0.8 -0.1 1.0

0.1 1.0 Change

Rimonabant

20 mg

Rimonabant

5 mg Placebo

Metformin Sulfonylureas

ITT, LOCF

n=111 n=106

n=204 n=211

0.1 1.1 7.4 1.4 7.3 1.0

Placebo

7.4 0.9 7.3 0.8

7.1 0.9 Baseline

6.9 0.9 6.6 0.8

7.2 1.0 Year 1

-0.7 (0.1)* -0.7 (0.1)*

Difference 20mg

v placebo (SEM)

-0.5 0.8 -0.6 0.8

0.1 1.0 Change

Rimonabant

20 mg

Rimonabant

20 mg Placebo

%

0.1 1.1 7.4 1.4 7.3 1.0

Placebo

7.4 0.9 7.3 0.8

7.1 0.9 Baseline

6.9 0.9 6.6 0.8

7.2 1.0 Year 1

-0.7 (0.1)* -0.7 (0.1)*

Difference 20mg

v placebo (SEM)

-0.5 0.8 -0.6 0.8

0.1 1.0 Change

Rimonabant

20 mg

Rimonabant

20 mg Placebo

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

Exenatide and glycemic control added tocombination therapy with Metformin and

a Sulfonylurea in Type 2 Diabetes

Kendall et al, Diabetes Care 28 (2005) 1083-91

GLP-1 breakdown by DPP IV

Holst, Diabetologia 48(2005) 612-15

Inhibition of DPP-4 Increases Active GLP-1

Intestinal GLP-1 release

GLP-1 inactive

Meal

Active GLP-1

DPP-4 inhibitor

DPP-4

Intestinal GLP-1 release

GLP-1 inactive

Meal

Active GLP-1

DPP-4 inhibitor

DPP-4

Adapted from Rothenberg P, et al Diabetes 2000;49(suppl 1):A39.

T ime (min)

P lacebo

L A F 237 5.0

8.0

11.0

14.0

50 75 100 125

8.0

11.0

14.0

50 75 100 125

Vildagliptin (LAF237) Reduces HbA1c Over 1 Year

PBO/MET (core, ITT n = 51)

PBO/MET (core, ITT n = 51)

Mean Efficacy of Pharmacotherapeutic Options in Type 2 Diabetes

Capacity (%) 1.0

modified from Riddle MC.Diabetes Care 1990;13:676-686

Prandial insulin approach in

type 2 diabetes

Mealtime glucose spikes Fasting hyperglycaemia Normal

Time (hours)

T i m e a c t i o n p r o fil e o f v a r i o u s i n s u l i n a n d i n s u l i n

a n a l o g u e s a s s e s s e d b y e u g l y c e m i c g l u c o s e

c l a m p i n n o r m a l s u b j e c t s

Bruttomesso et al Diabetes 1999; 48:

Targeting postprandial glycemia with rapid acting insulin

hyper-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

Airway Delivery of

Inhaled Insulin

Various Inhalation Systems

For Insulin

KOS Pfizer/Aventis/Nektar Aradigm/Novo Nordisk

Mannkind

Aerogen

Lilly/Alkermes

Bronchiale und alveoläre Resorptionsfläche

Alveolen

Bronchialsystem

Alveolen

0 2 4 6 8 10 12

Lispro Regular insulin Inhaled insulin

Superiority (109, 110)

Phase 3 Studies (106, 107, 108, 109, 110)

Type 1

(106, 107) Type 2 (108)

Type 2 (109, 110)

TZD vs Exubera

Failing Diet/Exercise

Overview: Phase 3 program

Inhaled insulin:

dosing in mg

1 mg approximately 2.75 I.U.

3 mg approximately 8.0 I.U.

Insulin pretreated type 2 diabetes

Hollander et al Diabetes Care (2004)27:2356

• Lung Function (some changes statistically

significant, but clinically not relevant)

• Approved only in non – smokers (!)

• Insulin antibody formation(Igg, binding % in

• Longterm safety (?)

Inhaled insulin may be used as short acting

shortly prior to meals.

Longterm safety needs to be monitored

further by good longterm post-marketing surveillance.

Emerging therapies – do they bring advances for better management of type 2 diabetes?

1) efficacy of pharmacotherapy options?

2) preservation of beta-cell function?

3) understanding of pathophysiology?

4) Side effect profile?

5) self management by the patient?

6) longterm outcome?

Better?

0 10 20 30 40 50 60 70 80 90 100

Rihl, Biermann, Standl: Diabetes & Stoffw (2002)11:150-158

IRIS-Study (representative cohort of 4575 type 2 diabetic patients

in Germany): Proportion of patients achieving specific HbA1c targets

HbA1c target

Policy of selecting the appropriate

antidiabetic therapy according to the

metabolic situation

short acting sulphonylurea, Glinide, short acting regular insulin or insulin analog, respectively

long acting sulphonylurea, glitazone, long acting insulin or insulin analog, respectively

alpha-glucosidase inhibitor

sulphonylurea, glinide, Insulin Insulin deficiency

Standl et al, Diabetologia (2003) 46 Suppl 1:30-36