Established and Novel Pharmacological Therapies

for Type 2 Diabetes

McGill First Canadian Summit onSurgery for Type 2 Diabetes

Montréal, QuébecMay 6, 2010

David C.W. Lau, MD, PhD, FRCPCProfessor of Medicine and Biochemistry

Julia McFarlane Diabetes Research CentreUniversity of Calgary

Email: dcwlau@ucalgary.ca

Disclosures

• Research funding:CIHR, AHFMR, Alberta Cancer Board, AstraZeneca, BMS, Dainippon, GSK, Eli Lilly, Pfizer and sanofi-aventis

• Consultant or advisory board member: Abbott, Allergan, AstraZeneca, Bayer, Boehringer-Ingelheim, GSK, Eli Lilly, Merck, Novartis, Novo Nordisk, Pfizer, Roche, sanofi-aventis, Sepracor

• Speaker bureau:CDA, HSFC, AstraZeneca, Abbott, Bayer, Boehringer-Ingelheim, Eli Lilly, GSK, Merck, Novo Nordisk, Pfizer sanofi-aventis and Sepracor

Overview

• Glycemic control and vascular complications • Pathophysiology of type 2 diabetes• 2008 CDA Clinical Practice Guidelines on the

management of type 2 diabetes• Pharmacotherapy for type 2 diabetes• Novel and emerging therapies for type 2 diabetes

1 Fong DS, et al. Diabetes Care. 2003; 26 [Suppl. 1]:S99–S102.2 Molitch ME, et al. Diabetes Care. 2003; 26 [Suppl.1]:S94–S98.3 Kannel WB, et al. Am Heart J. 1990; 120:672–676.4 Gray RP & Yudkin JS. In Textbook of Diabetes. 1997.5 Mayfield JA, et al. Diabetes Care. 2003;26 [Suppl. 1]:S78–S79.

DiabeticretinopathyLeading causeof blindness in working-age adults1

DiabeticnephropathyLeading cause of end-stage renal disease2

Cardiovasculardisease

Stroke2- to 4-fold increase in cardiovascular mortality and stroke3

DiabeticneuropathyLeading cause of non-traumatic lower extremity amputations5

8/10 diabetic patients die from CV events4

Diabetes is a Serious Chronic Disease

P Hossain et al. N Engl J Med 2007;356:213-215

Global Increase 180 472 million!

Global Prevalence of Diabetes in 2000 and Projections for 2030

Obesity as the Major Cause of Diabetes

IDF. Diabetes Atlas. Second Edition 2003

Glycemic Control and Complications

DCCT: Type 1 diabetes followed for 6.5 years A1C 7% versus 9% 60% reduction in microvascular

complications 1

DCCT-EDIC 17-year follow-up 57% reduction in major CVD outcomes 2

UKPDS: Type 2 diabetes followed for 10 yrs A1C 7% versus 7.9% 25% reduction in microvascular

complications 3

Each 1% decrease in A1C ~30% reduction in microvascular complications in both Type 1 and Type 2 diabetes

1. DCCT Research Group. N Engl J Med 1993;329:977-862. DCCT/EDIC Research Group. N Engl J Med 2005;353:2643-533. Holman RR et al. N Engl J Med 2008;359:1577-1589

UKPDS: Long-term Glycemic ControlCross-sectional, median values

UKPDS, Lancet 1998;352:837-853

06

7

8

9

0 3 6 9 12 15

HbA

1c (

%)

Years from randomisation

Conventional

Intensive

6.2% upper limit of normal range

8

A1C

7

Years 2 6 10

Stratton IM, et al. UKPDS 35. BMJ 2000;321:405–12

Perc

enta

ge in

crea

se in

rela

tive

risk

corr

espo

ndin

g to

a 1

% ri

se in

HbA

1C

**

Any diabetes-related

endpoint

21%

**

Diabetes-related death

21% **

All cause

mortality

14%*

Stroke

12%

**

Peripheral vascular disease†

43%

**

Myocardial infarction

14%

**

Micro-vascular disease

37%

**

Cataract extraction

19%

† Lower extremity amputation or fatal PVD* P = 0.035; **P < 0.0001

UKPDS 35: Decreased Risk of Diabetes-related complications with 1% in A1C

Glucose Lowering (A1C 0.9%) and Non-fatal MIs

Ray KK et al. Lancet 2009;373:1765-1672

17%

Glucose Lowering (A1C 0.9%) and CAD

Ray KK et al. Lancet 2009;373:1765-1672

15%

The (DCCT/EDIC) Study Research Group. N Engl J Med 2005;353:2643-2653

DCCT/EDIC in DM1: 17-yearCumulative Incidence of First CV Event

Legacy effect; benefit of

early aggressive glycemic control on

CVD outcomes

DCCT/EDIC Research Group. N Engl J Med 2005;353:2643-53

ACE42%

CVD

57%

Holman RR, et al. N Engl J Med 2008;359:1577-1589

UKPDS 10-year Follow-up:Kaplan-Meier Curves for Outcomes

Legacy effect; benefit of

early aggressive glycemic control on

CVD outcomes

Holman RR, et al. N Engl J Med 2008;359:1577-1589

Ins-SU

End-pt9%

MI15%

Micro24%

Death13%

Met

End-pt21%

MI33%

MicroNS

Death27%

STENO-2 13-year Follow-up:Kaplan-Meier Curves of the Risk of Death and CV Events

All cause 45%

CVD

57%

Defining Glycemic Control

Parameter Target Rationale

A1C ≤ 7% (0.070 lab value)

A1C levels >7% are associated with significantly increased risk of microvascular and macrovascular complications

FPG 4.0–7.0 mmol/L FPG levels are a major contributor to A1C values of >8.5%

2h PPG 5.0–10.0 mmol/L(or 5.0–8.0 mmol/L)

In A1C levels approaching ≤7%, there is a greater contribution from postprandial glucose levels; if A1C targets are not met, lowering PPG to 5.0–8.0 mmol/L can be considered

2008 CDA CPGs. Can J Diabetes 2008;32(Suppl 1):S29–S31

A1C = glycated hemoglobin FPG = fasting plasma glucose PPG = postprandial plasma glucose

Targets for Glycemic Control

• In most people with type 1 or type 2 diabetes, A1C ≤ 7% should be targeted to reduce microvascular complications [Grade A, Level 1A]

• In type 2 diabetes, A1C ≤ 6.5% may be considered to further lower the risk of nephropathy [Grade A, Level 1A]

Can J Diabetes 2008;32(Suppl 1):S29-S31

Intestine:Glucose Absorption

Liver: Glucose Production

Muscle

Fat

PeripheralGlucoseUptake

Pancreas

InsulinSecretion

+

- +

Brain &Nervous System

BLOOD GLUCOSE

Control of Blood Glucose

Diminishedinsulin

HyperglycemiaLiver

1. Insulin deficiency

2. Excess glucose output 3. Insulin resistance

Pancreas

Muscle and fat

Excess glucagon

Islet

Diminishedinsulin

α-cell produces excess glucagon

β-cell produces less insulin

Pathophysiology of Type 2 DiabetesThree Main Defects

Adapted from Williams G, Pickup JC, eds. Handbook of Diabetes, 3rd ed. Malden, MA: Blackwell Publishing, 2004. DeFronzo RA. Ann Intern Med. 1999;131:281–303; Buse JB, et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003;1427–1483.

Pancreatic β-cells Sulfonylureas, meglitinides

↑ insulin release

Gut

α-glucosidase inhibitors glucose

absorption

Muscle

Liver

Biguanides Thiazolidinediones

Insulin glucose production

ThiazolidinedionesBiguanides

Insulin ↑ glucose uptake

Oral Anti-diabetic agents: Mechanisms of action

Amelioration of hyperglycemia

Insulin Secretion Profiles in Type 2 Diabetes and Non-Diabetic Subjects

K Polonsky et al. New Engl J Med 318:1231-1239, 1998

Pa

ncre

atic

Insu

lin S

ecr

etio

n (

pm

ol/m

in)

Clock Time (hours)

No Diabetes

Type 2 diabetes

Meals (9 am, 1pm, 6pm)

800

700

600

500

400

300

200

100

6:00 am 10:00 2:00 pm 6:00 10:00 2:00 am

β-ce

ll fu

nctio

n (%

)

Years

100

75

50

25

00 1 2 3 4 5 6

β-cell function declines, while . . .

UK Prospective Diabetes Study Group. Diabetes 1995;44:1249–1258

Years0 1 2 3 4 5 6

9

10

8

7

6

5

HbA

1C

. . . hyperglycemiaincreases

Progressive Impairment in β-cell FunctionDiet/conventional Rx (n=376)Metformin (n=159)Sulfonylurea/intensive (n=511)

Food intake

Stomach

GI tract

Intestine

Increases and prolongs GLP-1 effect on alpha-cells:

Alpha-cells

Pancreas

Insulin release

Net effect: Blood glucose

Beta-cells

Increases and prolongs GLP-1 and GIP effects on beta-cells:

DPP-4 inhibitor

Glucagon secretion

Incretins

DPP-4

DPP-4 Inhibitors Enhance Incretin and Insulin Secretion

Adapted from: Barnett A. Int J Clin Pract 2006;60:1454-70 Drucker DJ, Nauck MA. Nature 2006;368:1696-705Idris I, Donnelly R. Diabetes Obes Metab 2007;9:153-65

Lifestyle Intervention

A1C ≥9%

• Initiate pharmacotherapy immediately

• Consider initiating metformin concurrently with another agent from a different class;

• Initiate insulin

Symptomatic hyperglycemia with metabolic decompensation

Initiate insulin ± metformin

A1C <9%

Initiatemetformin

If not at target

2008 CDA CPGs. Can J Diabetes 2008;32(Suppl 1):S1–201

2008 CDA CPGs Treatment Algorithm

Initiate metformin

Initiate pharmacotherapy immediately without waiting for effect from lifestyle interventions: Consider initiating metformin concurrently with another agent from a different class; or insulin Initiate insulin

± metformin

If not at target

Add an agent best suited to the individual:

• Alpha-glucosidase inhibitor

• Incretin agent: DPP-4 inhibitor

• Insulin

• Insulin secretagogue: Meglitinide, Sulfonylurea

• TZD

• Weight loss agent

If not at target:

• Add another drug from a different class; or

• Add bedtime basal insulin to other agent(s); or

• Intensify insulin therapy

2008 CDA Clinical Practice GuidelinesClinical Assessment - Lifestyle intervention (Nutrition therapy and physical activity)

A1C < 9.0% A1C ≥ 9.0% Symptomatic hyperglycemia with metabolic decompensation

2008 CDA CPGs. Can J Diabetes 2008;32(Suppl 1):S53–S61

2008 CDA CPGs. Can J Diabetes 2008;32(suppl 1):S53-S61

* Less hypoglycemia in the context of missed meals

2008 CDA Clinical Practice Guidelines:Drug Therapy for Type 2 Diabetes

0 6 12 18 24 30 38 46 54 62 70 78 91 1046

6.5

7

7.5

8

8.5

9

Sitagliptin and Metformin Combination Therapy

24-Week Phase Continuation Phase Extension Phase

A1C

(LS

mea

n ch

ange

%)

Time (weeks)Sita 100 mg qd (n=50) Met 500 mg bid (n=64)

Met 1000 mg bid (n=87) Sita 50 mg bid + Met 500 mg b.i.d. (n=96)

Sita 50 mg bid + Met 1000 mg bid (n=105)

Adapted from Qi Daniel S, et al. 73-OR, EASD 2008Sita = sitagliptin; Met = metformin

Exenatide Monotherapy:A1C Change from Baseline

0

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.04 8 12 16 24

Study Week

LS M

ean

(SE

)

in A

1C (

%)

*

*

*

*

*

*

*

*

ITT patients. Analysis using mixed-models repeated measures. Mean baseline A1C values (%): exenatide 5 g: 7.9%;exenatide 10 g: 7.8%; placebo: 7.8%. *P ≤ 0.001 vs. placebo. ITT=intent-to-treat. LS=least-squares. SE=standard error.

Adapted from Moretto TJ, et al. Clin Ther. 2008;30(9):1448-1460.

Exenatide 5 µg (n=76)Exenatide 10 µg (n=76)Placebo (n=75)

Exenatide Monotherapy: Weight Change from Baseline

-4.0

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.00 4 8 12 16 24

LS M

ean

(SE

)

in W

eigh

t (kg

)

Study Week

†

*

†

*

*

*

Exenatide 5 µg (n=77)Exenatide 10 µg (n=76)Placebo (n=76)

ITT patients. Analysis using mixed-model repeated measures. Mean baseline weights: 85 to 86 kg.Statistical comparisons are vs. placebo. *P ≤ 0.007. †P ≤ 0.027. ITT=intent-to-treat. LS=least-squares. SE=standard error

Adapted from Moretto TJ, et al. Clin Ther. 2008;30(9):1448-1460.

Kahn SE et al. N Engl J Med 2006;355:2427-2443

ADOPT: Kaplan-Meier Estimates of the Cumulative Incidence of Monotherapy Failure at 5 Years

SGLT2 Inhibitor

• Sodium–glucose cotransporter-2 (SGLT2) reabsorbs glucose in the proximal tubule

• Dapagliflozin induces glucosuria by inhibiting sodium–glucose cotransporter-2

• Insulin-independent glucose lowering

• Lowers A1C by 0.6-0.8%• 2-3% body weight loss

Komoroski B et al. Clinical Pharm & Therapeutics 2009;85:513–519

Glucokinase Activators

Glucokinase Activators

• Glucokinase serves as a glucose sensor of the pancreatic islet β cells‐

• Controls the conversion of glucose to glycogen in the liver and regulates hepatic glucose production

• Lowers glucose by stimulating insulin release and glucose uptake in liver

• Can be used in combination with other OHAsMatchinski F Nature Rev Drug Discovery 2009;8;399-416

Pharmacotherapy for Type 2 Diabetes

• Glycemic control is an integral component of optimal diabetes management

• Metabolic control also reduces cardiovascular disease risk in people with diabetes

• Availability of effective and safe drugs that lower glucose without significant adverse effects will add to current armamentarium

Thank you

Questions?