Page 1: Baker IDI

Update on therapies for type 2 diabetes

Page 2: Baker IDI

Treatment algorithms for type 2 diabetes

Page 3: Baker IDI

Basal Premixed

Basal Bolus insulin

Sulphonylurea

Acarbose DPP-4 inhibitor # Glitazone* Insulin

Lifestyle Modification•diet modification•weight control•physical activity

Metformin

Management Algorithm for Blood Glucose Control in Type 2 Diabetes in Australia

• The algorithm includes only therapeutic agents available through the PBS.• If HbA1c >7% consider intensifying treatment provided hypoglycaemia is not a problem.# Authorised only as dual therapy with metformin or sulphonylurea where combination metformin and sulphonylurea

is contraindicated or not tolerated.* Rosiglitazone is not authorised for triple therapy or for use with insulin (from February 1, 2009) but is approved only as dual

therapy with metformin or sulphonylurea where combination metformin and sulphonylurea is contraindicated or not tolerated.

Targets for type 2 diabetes in Australia

• Glycaemic control

– HbA1c <7.0%

• Blood pressure*

– <130/80 mmHg

– <125/75 mmHg in the presence of proteinuria

• Lipids*

– LDL >2.5 mmol/l – consider statin

– TG >2.0 mmol/l – consider fibrate

• Aspirin for those with prior CVD, and those with other CVD risk factors

* NHMRC 2005

ADA/EASD algorithm 2009

aSulfonylureas other than glybenclamide (glyburide) or chlorpropamide.bInsufficient clinical use to be confident regarding safety.

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

Stepwise Use of Medication

Monotherapy

Combination OHA

Insulin + OHA

HbA1c > 7.0%

MetforminSulphonylureaMetforminSulphonylurea2 or more of: Metformin Sulphonylurea Acarbose Glitazone Glinide GLP1 DPPIV

2 or more of: Metformin Sulphonylurea Acarbose Glitazone Glinide GLP1 DPPIV

MetforminSulphonylureaGlitazone

MetforminSulphonylureaGlitazone

Thiazoledinediones – Australian PBS restrictions

• Dual therapy, ie. rosiglitazone or pioglitazone, when SU or metformin contra-indicated or causes adverse event

• Triple oral therapy NOW pioglitazone only!

• Can be combined with insulin NOW pioglitazone only!

• HbA1c must be >7.0% at initiation• Precautions: fluid retention, bone loss, (?coronary

events with rosigltazone)

Page 8: Baker IDI

Insulin initiation in type 2 diabetes

2 4 6 8

Hours after Injection

0.5

2.5

0

Hours after injection

2 4 6 8

Insu

lin A

ctio

n

Regular Insulin(Actrapid,Humulin R)

HumalogNovoRapid

Apidra

0

Hours after injection

10 12

Quick-acting insulins

2 4 6 8

Hours after Injection

0.5

2.5B

lood

Insu

lin L

evel

0 4 12 16

Hours after injection

8

Blo

od In

sulin

Lev

el

0 20 24

ProtaphaneHumulin NPH Lantus

Levemir

Long-acting insulins

Page 11: Baker IDI

Basal Premixed

Basal Bolus insulin

Sulphonylurea

Acarbose DPP-4 inhibitor # Glitazone* Insulin

Lifestyle Modification•diet modification•weight control•physical activity

Metformin

Management Algorithm for Blood Glucose Control in Type 2 Diabetes in Australia

• The algorithm includes only therapeutic agents available through the PBS.• If HbA1c >7% consider intensifying treatment provided hypoglycaemia is not a problem.# Authorised only as dual therapy with metformin or sulphonylurea where combination metformin and sulphonylurea

is contraindicated or not tolerated.* Rosiglitazone is not authorised for triple therapy or for use with insulin (from February 1, 2009) but is approved only as dual

therapy with metformin or sulphonylurea where combination metformin and sulphonylurea is contraindicated or not tolerated.

Consensus statement EASD ADA 2008

Page 13: Baker IDI

Insulin initiation trials

Diabetes Care 2003, Riddle et al.

Minor hypoglycaemia 43% vs. 16% BiAsp vs. Glargine

Diabetes Care 2005, Raskin et al.

Page 21: Baker IDI

Why new treatments?

What’s wrong with the old treatments?

Page 22: Baker IDI

New treatments - why new treatments?

• Beta cell preservation– Prevent relentless progression of type 2 diabetes

• Hypoglycaemia ? harmful• CV morbidity and mortality

– ACCORD and other CV outcome trials– Glitazone controversies

• Weight loss as a priority – Recognized as a major factor in morbidity

Page 23: Baker IDI

Incretins

• GLP 1 analogues• Exenatide• Liraglutide• Once weekly GLP – 1 analogues

• DPP 4 inhibitors• Sitagliptin

Page 24: Baker IDI

The Incretin Effect Demonstrates the Response to Oral vs IV Glucose

Mean ± SE; N = 6; *p.05; 01-02 = glucose infusion time.Nauck MA, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986;63:492-498. Copyright 1986, The Endocrine Society.

Ven

ou

s P

lasm

a G

luco

se (

mm

ol/L

)

Time (min)

C-p

epti

de

(nm

ol/L

)

11

5.5

001 60 120 180 01 60 120 180

0.0

0.5

1.0

1.5

2.0

Time (min)02

02

Incretin Effect

Oral Glucose IV Glucose

**

*

*

**

*

The Incretin Effect Is Reduced in Patients With Type 2 Diabetes

0

20

40

60

80

Insu

lin (

mU

/L)

0 30 60 90 120 150 180

Time (min)

** *

** **

0

20

40

60

80

0 30 60 90 120 150 180

Time (min)

**

*

*p≤.05 compared with respective value after oral load. Nauck MA, et al. Diabetologia. 1986;29:46-52. Reprinted with permission from Springer-Verlag © 1986.

Patients With Type 2 DiabetesControl Subjects

Intravenous GlucoseOral Glucose

GLP-1 Effects in Humans: Understanding the Glucoregulatory Role of Incretins

Promotes satiety and reduces appetite

Beta cells:Enhances glucose-dependent insulin

secretion

Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520.; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.; Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553.; Adapted from Drucker DJ. Diabetes. 1998;47:159-169.

Liver: ↓ Glucagon reduces

hepatic glucose output

Alpha cells:↓ Postprandial

glucagon secretion

Stomach: Helps regulate

gastric emptying

GLP-1 secreted upon the ingestion of food

28

Exenatide (Exendin-4)• Synthetic version of salivary

protein found in the Gila monster• Approximately 50% identity with

human GLP-1 Binds to known human GLP-1

receptors on cells in vitro Resistant to DPP-4 inactivation

Development of Exenatide: An Incretin Mimetic

Adapted from Nielsen LL, et al. Regulatory Peptides. 2004;117:77-88. With permission from Elsevier for English use only.; Drucker DJ. Diabetes Care. 2003;26:2929-2940.; Ahrén B. Best Pract Res Clin Endocrinol Metab. 2007;21:517-533.

Site of DPP-4 Inactivation

H G E G T F T S D L S K Q M E E E A V R L F I E W L K N G G P S S G A P P P S – NH2

H A E G T F T S D V S S Y L E G Q A A K E F I A W L V K G R – NH2

Exenatide

GLP-1Human

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Exenatide once weekly

• Once weekly vs bd exenatide, 30 week study• Patients were drug naive or treated with 1 or more oral glucose-

lowering therapies (~15% diet/exercise, ~45% 1 OAD, ~40% 2 OADs).

• Starting HbA1c 8.3±1.0%• HbA1c decreased in both groups , 1.9%±0.08 vs 1.5%± 0.08

(P=0.002) in once weekly vs bd

• 22 week extension study LAR for all patients after first 30 weeks• At 52 weeks decrease HbA1c by 2.0% both groups, 4.1 kg wt loss ,

80% patients lost weight BP decreased 4-6 mmHg

Page 32: Baker IDI

DPP 4 inhibitors

Adapted from Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913; Ahrén B. Curr Diab Rep. 2003;2:365–372; Drucker DJ. Diabetes Care. 2003;26:2929–2940; Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441.

Ingestion of food

β cellsα cells

Release of gut hormones —

incretins*

PancreasGlucose-dependent

Insulin from β cells(GLP-1 and GIP)

Glucose uptake by muscles

Glucose dependent Glucagon from

α cells(GLP-1)

GI tractActive

GLP-1 & GIP

DPP-4 enzyme

InactiveGIP

InactiveGLP-1

*Incretins are also released throughout the day at basal levels.

Glucose production

by liver

Blood glucose in fasting and postprandial states

10

Clinical experience with sitagliptin

• Effective for dual , triple therapy and with insulin

• Low side effect profile

• Weight neutral

• No hypoglycaemia in combination with metformin or

glitazone

• Safe and effective in older patients

Januvia -PBS restrictions in Australia

• Dual therapy for combination with metformin or a sulphonylurea agent

• HbA1c > 7.0% at initiation

• Treatment with metformin or sulphonylurea as a second agent is either contraindicated or not tolerated

• (private script $100 per month)

Page 36: Baker IDI

Other new agents

•SGLT 2 inhibitors•Glucokinase activators•Glucagon receptor antagonists