TYPE 2 DIABETES

Diagnosis

• ADA criteria 1997

Random plasma glucose >11.1mmol/l with symptoms

orFasting plasma glucose(FPG) >7.0 mmoll-1

or2 hour plasma glucose (OGTT) >11.1 mmoll-1

each must be confirmed on a subsequent day

Diabetes: WHO

• Diabetes Mellitus-FPG or 2HPG or both

• Impaired glucose tolerance-FPG and 2HPG

• Impaired fasting glucose-FPG <7 mmoll-1 and 2HPG < 7.8 mmoll-1

Pathophysiology

• Insulin resistance and relative insulin deficiency/ defective secretion

• Not immune mediated• No evidence of β cell destruction• Increased risk with age, obesity and ↓

physical activity• Strong genetic predisposition

Adapted from 2. Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483; 3. Buchanan TA Clin Ther 2003;25(suppl B):B32–B46; 4. Powers AC. In: Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, 2005:2152–2180; 5. Rhodes CJ Science 2005;307:380–384.

The pathophysiology of type 2 diabetes

HyperglycaemiaLiver

Insulin deficiency

Excess glucose output Insulin resistance (decreased glucose

uptake))

Pancreas

Muscle and fat

Excess glucagon

Islet

Diminishedinsulin

Diminishedinsulin

Alpha cellproduces excess glucagon

Beta cellproduces less insulin

Presentation

• Insidious onset (asymptomatic many yrs)• generally not ketosis• Tendency to be obese• Macrovascular/microvascular complications

at presentation• Not insulin dependent but may be insulin

requiring

Specific types of diabetes

• Genetic defects of β cell insulin secretory defects (MODY genes), mitochondrial DNA (MELAS)

• Diseases of exocrine pancreaspancreatitis, cancer, haemachromatosis, cystic fibrosis

• Endocrinopathiescushings, acromegaly, phaeochromocytoma

Current Treatment Type 2 Diabetes

Diet, Lifestyle change and Metformin

Sulphonlyurea

Poglitazone

Metformin Intolerant

Or

HbA1C ≥ 7 %

Add

On Triple Therapy

Insulin Regimens

New Therapy

New Therapy

Development of Oral Therapies

• Sulphonlyurea The hypoglycemic action of sulphamides was discovered in 1945

• Metformin was first described in the scientific literature in 1957

• Thiazolidinedione sometimes referred to as 'glitazones' were introduced in 1997

Insulin 1922

Problems With Existing Therapies

• Sulphonlyurea Therapy

• Glitazone Therapy

• Insulin combinations

• Weight gain 2.6kg (UKPDS 1998)

• Weight gain 4.5 kg (obesity review 2007)

• 43 % ↑ Myocardial Infarction (NEJM 2007)

• Weight Gain 4 kg (UKPDS 1998)

Why Treat Diabetes

• Hyperglycaemia at diagnosis type 2 diabetes associated with increase risk of CVD (UKPDS, 1999)

• Hyperglycaemia after a glucose load shown to be associated with CVD (Whitehall, 1980, Honolulu, 1987)

• HbA1C associated with increase risk death from macrovascular disease (Finland, 1997,Germany, 1996)

• No threshold effect demonstrated

MI and Sudden Death

Mean HbA1c during follow-up

Haz

ard

ratio

14% decrease per 1% decrement in HbA1c

p=<0.0001

0.5

1

10

5% 6% 7% 8% 9% 10% 11%

Adjusting for:Adjusting for:AgeAgeEthnicityEthnicitySystolic PressureSystolic PressureAlbuminuriaAlbuminuriaSmokingSmokingHDL, LDL, TriglycerideHDL, LDL, Triglyceride

0

1

2

3

4

5

6

5 6 7 8 9 10Mean HbA1c(%) during follow-up

Microvascular Disease

Myocardial infarctionIncidence% per year

MI and Microvascular disease by HbA1c

UKPDSUKPDS

Adjusted to age,sex, ethnicity

n = 4585

UKPDS 35.BMJ 2000;321: 405-12

All Cause Mortality

0.5

1

4

5 6 7 8 9 10 11

Updated mean HbA1c (%)

14% decrement per 1% difference in HbA1c

p<0.0001HazardHazardratioratio

Treatment of Type 2 Diabetes

• First line– Diet and lifestyle changes and Metformin

• Second line– Sulphonlyura– Gliptins– Glitazone

• Third line– Add on any of above– Basal Insulin– BD Insulin

Metformin

• First line drug in all patients regardless of weight• Mechanism of action is reduction in hepatic

glucose output and increased insulin sensitivity• Not associated with hypoglycaemia• Start small dose (500mg) and titrate upwards

– With or after food to reduce side effects– Slow release metformin

• Sulphonlyurea, Glitazone, Gliptins and Insulin can be added to metformin therapy

• Renal failure

Sulphonlyurea Therapy

• Add on to Metformin• Lowers blood glucose by stimulating insulin

release• Can induce hypoglycaemia• Timing of dose not crucial but consider 30

min before breakfast (↓ plasma levels)• Role of sulphonlyureas in management is

changing

Glitazone Therapy

• New class of drug• Decreases glucose output by liver and

decreases peripheral insulin resistance• Two licensed at present which is restricted

– Rosiglitazine– Pioglitazone

• Time to effect ≈ 8 weeks• Contraindicated in liver disease and CCF

Rosiglitazone vs Pioglitazone

• Recent evidence rosiglitazone is associated with significant increase risk of MI and death from cardiovascular causes

• No such effect with Pioglitazone• Pioglitazone lower risk of deaths from MI,

stroke• Position statement risk vs benefits

Insulin Secretagogues

• Post prandial glucose regulators• Second line drugs• Rapid onset of action and short duration• Avoidance of hypoglycaemia• Nateglinide or Repaglinide

α Glucosidase Inhibitors

• Inhibit glucose absorption in small bowel• Effective in control of post prandial

hypoglycaemia• Cause GI upset

Incretin Effect (GLP-1 Pathway)

• described initially in 1964 it refers to the amplification of the insulin response to an oral glucose load

• The effect is mediated by two intestinally secreted hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) which act on specific receptors of the ß cells to produce insulin

GLP-1 effects in humans

Adapted from 1Nauck MA, et al. Diabetologia 1993;36:741–744; 2Larsson H, et al. Acta Physiol Scand 1997;160:413–422; 3Nauck MA, et al. Diabetologia 1996;39:1546–1553; 4Flint A, et al. J Clin Invest 1998;101:515–520; 5Zander et al. Lancet 2002;359:824–830.

GLP-1 secreted upon the ingestion of food

1.β-cell:enhances glucose-dependent

insulin secretion in the pancreas1

3.Liver:reduces hepatic glucose

output2

2.α-cell:suppresses postprandial

glucagon secretion1

4.Stomach:slows the rate of

gastric emptying3

5.Brain:promotes satiety and

reduces appetite4,5

Incretin Effect in Type 2 Diabetes

• The incretin effect is diminished in patients with type 2 diabetes

• GIP secretion is normal, but its action is diminished

• GLP-1 secretion is diminished, but its action is preserved

• Glucagon secreted from pancreatic α-cells is also elevated in type 2 diabetes (GLP-1 suppresses glucagon secretion from pancreatic α-cells in a glucose-dependent manner, suppressing hepatic glucose output)

Incretins and glycaemic control

Adapted from 7. Drucker DJ. Cell Metab. 2006;3:153–165. 8. Miller S, St Onge EL. Ann Pharmacother 2006;40:1336-1343.

Active GLP-1 and GIP

Release of incretin gut hormones

Pancreas

Bloodglucose control

GI tract

Glucagon from alpha cells

(GLP-1)Glucose dependent

Alpha cells

Increased insulin and decreasedglucagon reduce hepatic glucose output

Glucose dependentInsulin

from beta cells(GLP-1 and GIP)

Beta cells

Insulinincreases peripheral glucose uptake

Ingestion of food

DPP-4enzyme rapidly

degrades incretins

Gila Monster

The Gila monster is a venomous Lizard native to US and Mexico. Anadult Gila monster can consume its entire yearly energy budget in three or four mealsExendin-4 was discovered by serendipity in the salivary glands of the Gila monsterThe lizard hormone has 53% homology with human GLP-1

Therapeutic Agents using the GLP-I Pathway

• GLP-1 receptor agonists– Exenatide (naturally occurring but bioengineered)

– Liraglutide (GLP-1 analogue)

• DPP-IV Inhibitors– Sitagliptin – Vidagliptin– Saxagliptin

GLP-1• BYETTA® was authorised by the European Medicines

Evaluation Agency (EMEA) in November 2006• BYETTA® is indicated for the treatment of type 2 diabetes

mellitus in combination with metformin, and/or sulphonylureain patients who have not achieved adequate glycaemic control on maximally tolerated doses of these oral therapies

Exenatide Summary of Product Characteristics 2006Fixed dose, pre-filled pens

Overall incidence ≥5% and incidence of Exenatide > placeboBYETTA® (exenatide) US Prescribing Information, February 2007, data on file.

Results of 30-week exenatide studies

Placebo (N = 483)

Exenatide 5 µg and 10 µg BD

(N = 963)Nausea 18% 44%Vomiting 4% 13%Diarrhoea 6% 13%Feeling jittery 4% 9%Dizziness 6% 9%Headache 6% 9%Dyspepsia 3% 6%

Adverse events

Sitagliptin (DPP-4 inhibitor)• Sitagliptin is an orally administered DPP-4

inhibitor

• Improvement in glycaemic control is mediated by increasing the levels of active incretin hormones (GLP-1, GIP) leading to

• Decreased glucagon

• Increased insulin

• Sitagliptin improves glycaemic control as monotherapy or add on therapy to metformin or pioglitazone

Adverse Events

UncommonVomiting

UncommonDiarrhoea

UncommonAbdominal Pain

CommonNausea

commonUncommonHypoglycaemia

Sitagliptin and Pioglitazone

Sitagliptin and Metformin

D I A G N O S I S

A n d / O r

L I F E S T Y L E I N T E R V E N T I O N

A N D

M E T F O R M I N

c o n s id e r

A d d to

o r

O r

Y E S

A d dP IO G L IT A Z O N E

A d dP IO G L IT A Z O N E

O rS U L P H O N L Y U R E A P I O G L I T A Z O N E

S I T A G L I P T I N

M E T F O R M IN

P IO G L IT A Z O N E

S U L P H O N L Y U R E A

M E T F O R M IN

IN T O L E R A N T

H b A 1 C ≥ 7 %

O rO rS U L P H O N L Y U R E A P I O G L I T A Z O N E

S I T A G L I P T I N

M E T F O R M IN

P IO G L IT A Z O N E

S U L P H O N L Y U R E A

M E T F O R M IN

IN T O L E R A N T

H b A 1 C ≥ 7 %

O r

A d dB A S A L I N S U L I N

H b A 1 C ≥ 7 %

S to p S I T A G L IP T I N

tr ip le th e r a p yO r

A d d it io n o f s u lp h o n ly u r e a a n d /o r b a s a l in s u l in

O rIn te n s ife d in su l in r e g im e n e g

b a sa l p lu sA d d E x e n a t id e to S u lp h o n ly u r e a a n d

o r M e tfo rm in

H b A 1 C ≥ 7 %

H b A 1 C ≥ 7 %

A d dB A S A L I N S U L I N

A d dB A S A L I N S U L I N

H b A 1 C ≥ 7 %H b A 1 C ≥ 7 %

S to p S I T A G L IP T I N

tr ip le th e r a p yO r

A d d it io n o f s u lp h o n ly u r e a a n d /o r b a s a l in s u l in

O rIn te n s ife d in su l in r e g im e n e g

b a sa l p lu s

S to p S I T A G L IP T I N

tr ip le th e r a p yO r

A d d it io n o f s u lp h o n ly u r e a a n d /o r b a s a l in s u l in

O rIn te n s ife d in su l in r e g im e n e g

b a sa l p lu sA d d E x e n a t id e to S u lp h o n ly u r e a a n d

o r M e tfo rm inA d d E x e n a t id e to S u lp h o n ly u r e a a n d

o r M e tfo rm in

H b A 1 C ≥ 7 %

H b A 1 C ≥ 7 %

L ife s ty le c h a n g e a n d M e tfo rm in

D ia g n o s is

A d dP I O G L IT A Z O N E

H b A 1 C ≥ 7 %

Y E S

Summary

• Type 1 diabetes requires diet and insulin treatment

• Type 2 requires diet, oral hypoglycaemic agents and or insulin

• Choice is agent depends on patient weight and ability to tolerate drug

Any Questions ?