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Update 2010: Type 2 Diabetes. Afshan Zahedi , BASc, MD, FRCP(C) Endocrinology Medical Director, Diabetes Center The Scarborough Hospital Assistant Professor of Medicine University of Toronto November 6, 2010 The 8 th Annual GTA Primary Care Symposium. Learning Objectives.

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update 2010 type 2 diabetes

Update 2010: Type 2 Diabetes

Afshan Zahedi, BASc, MD, FRCP(C)

Endocrinology

Medical Director, Diabetes Center

The Scarborough Hospital

Assistant Professor of Medicine

University of Toronto

November 6, 2010

The 8th Annual GTA Primary Care Symposium

learning objectives
Learning Objectives

Understand current limitations in the treatment of type 2 diabetes

Overview of different treatments for Type 2 Diabetes

- selecting the second or third OHA

Role of incretin-based therapies - glucagon-like peptide-1 [GLP-1] agonists - dipeptidyl peptidase-4 [DPP-4] inhibitors

Role of Insulin in Type 2 Diabetes

slide3
Natural History of Type 2 Diabetes

Impaired

Glucose Tolerance

Undiagnosed

Diabetes

Known

Diabetes

Insulin Resistance

Insulin Secretion

Postprandial Glucose

Fasting Glucose

Microvascular complications

Macrovascular complications

4-7 Years

Ramlo-Halsted BA, et al. Clinical Diabetes 2000;18:80-85, with permission from The American Diabetes Association

cell function progressively declines
ß-cell Function Progressively Declines

100

Diabetes diagnosis

80

60

β-cell function (%, HOMA)

40

20

Extrapolation of β-cell function prior to diagnosis

0

–12

–10

–8

–6

–4

–2

0

2

4

6

8

Years from diagnosis

HOMA = homeostasis model assessment

Lebovitz HE. Diabetes Reviews 1999;7:139 UKPDS Group. Diabetes 1995;44:1249

rate of progression from igt to type 2 dm
Rate of Progression from IGT to Type 2 DM
  • The IDF estimates that among persons with IGT,
  • 40-50% will progress to
  • Type 2 DM within 10 years

www.idf.org Fact sheet on IGT accessed Mar 10 2006

slide6
Diabetes Prevention Program (DPP)

n=3234 People with IGT, age 25+, BMI 24+, 2.8 yrs follow up

↓31%*

↓58%*

What was done in the intensive lifestyle arm to achieve a 58% reduction in diabetes incidence?

*All comparisons significant by group sequential log rank test

DPP Research Group. N Engl J Med 2002;346:393-403, with permission

slide7
Intensive Lifestyle Arm of the DPP

Goal: Lose 7% of initial body weight

Adopt a low calorie, low fat diet

Exercise a minimum of 150 minutes/week

How:Attend 16 diet, exercise and behaviour modification sessions taught by case managers on a one to one basis

Attend monthly individual sessions + other group sessions.

Results: 38% lost 7% or more of their initial body weight

58% exercised a minimum of 150 minutes/week

Daily energy intake dropped by 450 kcal

Fat intake dropped 6.6%

DPP Research Group. N Engl J Med 2002;346:393-403

the pathophysiology of type 2 diabetes includes three main defects
The Pathophysiology of Type 2 Diabetes Includes Three Main Defects

Islet

Pancreas

α-cell produces excess glucagon

β-cell produces less insulin

1. Insulin deficiency

Excess glucagon

Muscle and fat

Hyperglycemia

Diminishedinsulin

Diminishedinsulin

Liver

3. Insulin resistance

2. Excess glucose output

mechanisms of action of currently available oral hypoglycemic agents
Mechanisms of Action of Currently Available Oral Hypoglycemic Agents

Pancreatic β-cells

Liver

  • Sulfonylureas, meglitinides, incretins
  • Stimulate insulin release

Amelioration of hyperglycemia

Muscle

  • α-glucosidase inhibitors
  • Retard glucose reflux into circulation
  • PPARs (thiazolidinediones or glitazones)
  • Biguanides
  • Insulin
  • Incretins
  • Stimulate glucose uptake
  • Biguanides
  • PPARs (thiazolidinediones or glitazones)
  • Insulin
  • Incretins
  • Inhibit glucose production

Gut

PPAR = peroxisome proliferator-activated receptor agonist

Adapted from Williams G, Pickup JC, eds. Handbook of Diabetes. Blackwell Publishing; 2004 DeFronzo RA. Ann Intern Med 1999;131:281 Buse JB, et al. In: Williams textbook of endocrinology. Saunders; 2003:1427

slide11
Add an agent best suited to the individual based on the advantages / disadvantages listed below (agents listed in alphabetical order)

* Less hypoglycemia in the context of missed meals

2008 CDA Guidelines

choosing the next oha
Choosing the next OHA
  • Diabetes is a progressive disease
  • Three goals for treatment
    • Slow progression of Disease
    • Meet Glucose targets (ie A1C < 7 %)
    • Prevent diabetes complications
  • Three factors to consider
    • Risk of hypoglycemia
    • Weight Gain
    • Cost and coverage
slide13
ADOPT (A Diabetes Outcome Progression Trial): Study Design n=4360 pts, age 30-75, diagnosed with T2DM in the last 3 yrs, FPG 7.0 - 10.0 mmol/L, on lifestyle management alone at baseline

Run-In

4 weeks

Treatment Period

4-6 yrs

Rosiglitazone n=1456 Completed: 917 (63%)

Diet/exercise reinforcement

Metformin n=1454 Completed: 903 (62%)

Glyburide n=1441 Completed: 807 (56%)

Clinic visits every 2 months for 1 yr, then every 3 months

Randomization

Study end

Viberti G, et al. Diabetes Care 2002;25:1737-43

Khan SE, et al. N Engl J Med 2006;355(23):2427-43

adopt durability of glycemic control a1c progression over 5 years
ADOPT: Durability of Glycemic Control –A1C Progression Over 5 Years

Annual rate of increase in A1C (after initial 6 months):

Glyburide = 0.24%*

Metformin = 0.14%*

Rosiglitazone = 0.07%

*p<0.001 vs. rosiglitazone

Khan SE, et al. N Engl J Med 2006;355(23):2427-43, with permission

adopt primary outcome time to monotherapy failure
ADOPT: Primary Outcome Time to Monotherapy Failure

Incidence of Monotherapy Failure (FPG > 10.0 mmol/L) at 5 yrs:

15% with rosiglitazone

21% with metformin

34% with glyburide

Rosiglitazone vs. Metformin:

32% risk reduction*

Rosiglitazone vs. Glyburide:

63% risk reduction*

* p<0.001 for both comparisons

Khan SE, et al. N Engl J Med 2006;355(23):2427-43, with permission

adopt durability of glycemic control number of months to exceed a1c target of 7
ADOPT: Durability of Glycemic Control Number of Months to Exceed A1C Target of > 7%

Months

Khan SE, et al. N Engl J Med 2006;355(23):2427-43

adopt therapeutic considerations weight change over time
ADOPT Therapeutic Considerations: Weight Change Over Time

Khan SE, et al. N Engl J Med 2006;355(23):2427-43, with permission

add on to metformin pioglitazone vs gliclazide change from baseline in a1c and fpg 1 yr results
Add on to Metformin: Pioglitazone vs. GliclazideChange from Baseline in A1C and FPG – 1 yr results

n = 313

n = 317

FPG reduction at 52 weeks:

2.1 mmol/l (P+M)

1.6 mmol/l (G+M) [P=0.506]

HbA1C reduction at 52 weeks:

0.99% (P+M)

1.01% (G+M) [P=0.837]

Maximum decrease in HbA1C:

24 weeks (P+M)  maintain

16 weeks (G+M)  deteriorate at 16 weeks

Maximum reduction in FPG:

16 weeks (P+M)  maintain

8 weeks (G+M)  deteriorate at 32 weeks

Matthews D, et. al. Diabetes Metab Res Rev 2005; 21:167-174

slide19
Initial Monotherapy with Pioglitazone or Gliclazide – A1C over Two Years n=567 People with Type 2 Diabetes, age 35-75, 2 year follow-up

9

8.5

8

7.5

7

6.5

N=289

Pioglitazone

N=261

  • p <0.001
  • ‡ p <0.01
  • † p <0.05

*

N=251

Gliclazide

*

*

N=246

Hb1c (%)

N=128

N=266

*

N=238

N=140

*

N=157

N=237

N=203

N=271

N=246

N=237

N=259

N=268

N=237

N=175

N=147

N=198

N=154

N=267

N=232

N=230

N=269

N=262

I I I I I I I I I I I I I

0 4 8 12 16 24 32 42 52 65 78 91 104

Weeks of Treatment

Tan MH, et al. Diabetes Care 2005; 28: 544-550

incretin based therapies

Incretin-based Therapies

glucagon-like peptide-1 [GLP-1] agonists & dipeptidyl peptidase-4 [DPP-4] inhibitors

what are incretins
What Are Incretins?

Gut peptide hormones (GLP-1 and glucose-dependent insulinotropic peptide [GIP])

Secreted in response to food ingestion

Stimulate glucose-dependent insulin secretion

Account for up to 60% of insulin response in healthy subjects

Short half-life due to enzymatic degradation by DPP-4

glp 1 modes of action in humans
GLP-1 Modes of Action in Humans

Upon ingestion of food:

  • GLP-1 is secreted from the L-cells in the intestine

This in turn:

  • Stimulates glucose-dependent insulin secretion
  • Suppresses glucagon secretion
  • Slows gastric emptying
  • Reduces food intake / increases satiety

Long-term effects demonstrated in animals:

  • Increases β-cell mass and maintains β-cell efficiency

Drucker DJ. Curr Pharm Des 2001;7:1399Drucker DJ. Mol Endocrinol 2003;17:161

the family of incretin based therapies
The family of incretin-based therapies

Incretin-based therapies

GLP-1 Receptor Agonists

GLP-1

enhancers

DPP – IV

Inhibitors

Human GLP-1

Analogues

Exendin-based

Therapies

glp 1 secretion and inactivation
GLP-1 Secretion and Inactivation

Meal

Intestinal

GLP-1

release

GLP-1 t½ = 1 to 2 min

ActiveGLP-1

DPP-4

GLP-1

inactive

(>80% of pool)

GLP-1 = glucagon-like peptide–1; DPP-4= dipeptidyl-peptidase–4

Adapted from Deacon CF, et al. Diabetes. 1995;44:1126-1131.

glp 1 homology
GLP-1 Homology

100

80

60

43%

40

8.6%

20

0

Liraglutide1

Exenatide + Metformin2

Percentage of patients with increase in antibodies

97% amino acid homology to human GLP-1

Improved PK: albumin binding through acylation; heptamer formation

There was no blunting of efficacy by liraglutide antibodies

Slow absorption from subcutis

Resistant to DPP-4

Long plasma half-life (T½=13 h)

53% amino acid homology to human GLP-1

Study duration: liraglutide 26 weeks; exenatide 30 weeks

1. LEAD 1, 2, 3, 4, 5 meta-analysis of antibody formation. Data on file

2. DeFronzo et al. Diabetes Care 2005;28:1092

incretin therapies

Incretin Therapies

Glycemic Control

dpp 4 inhibitor a1c with sitagliptin monotherapy
DPP-4 Inhibitor A1C With Sitagliptin Monotherapy

Placebo

Sitagliptin 100 mg qd (n = 238)

Sitagliptin 200 mg qd (n = 250)

8.6

8.4

8.2

8.0

7.8

7.6

7.4

7.2

7.0

0

6

12

18

24

100 mg qd vs placebo = -0.79%*

200 mg qd vs placebo = -0.94%*

A1C (%)

Weeks

*Difference in LS mean change from baseline vs placebo at Week 24;p< 0.001

Aschner P, et al. Diabetes Care 2006;29:2632

a1c reduction with liraglutide monotherapy
A1C Reduction With LiraglutideMonotherapy

0.4

0.2

0.0

-0.2

-0.4

-0.6

-0.51

A1C change from baseline (%)

-0.8

-0.84*

-1.0

-1.14*

-1.2

*p < 0.001 vs Glimepiride

-1.4

-1.6

Liraglutide 1.2 mg

Liraglutide 1.8 mg

Glimepiride (SU)

Garber A, et al. Lancet 2008 Sep 24 [Epub]

a1c reductions with liraglutide metformin
A1C Reductions with Liraglutide + Metformin

+ metformin

0.4

0.2

0.1

0.0

-0.2

-0.4

-0.6

A1C change from baseline (%)

-0.8

-1.0

-1.0†

-1.0

-1.0†

-1.2

-1.4

-1.6

Placebo

Liraglutide 1.2 mg

Liraglutide 1.8 mg

Glimepiride (SU)

†p<0.05 versus placebo;

Nauck, et al. Diabetes Care, accepted for publication

Liraglutide is not yet available in Canada

a1c reductions with liraglutide su met tzd or met su
A1C Reductions with Liraglutide + SU, +Met/TZD or +Met/SU

+ SU

+ met + TZD

+ met + SU

0.23

-0.24

-0.44

-0.54

-1.08‡§

-1.09

-1.13‡§

-1.33¶

-1.48

-1.48

Placebo

Liraglutide 1.2 mg

Liraglutide 1.8 mg

Rosiglitazone (TZD)

Glargine

‡p<0.0001 versus placebo; §p<0.0001 versus rosiglitazone; ¶p=0.0015 versus glargine

0.4

0.2

0.0

-0.2

-0.4

A1C change from baseline (%)

-0.6

-0.8

-1.0

-1.2

-1.4

-1.6

Marre, et al. Diabetes 2008;57(suppl 1):A4;

Zinman b, et al. Diabetologia 2008;51(suppl 1):Poster 898;Russell-Jones, et al. Diabetes 2008;57(suppl 1):A159

Liraglutide is not yet available in Canada

most common adverse reactions associated with incretin based agents in phase iii trials
Most common adverse reactions associated with Incretin-based agents in Phase III Trials

*Not yet approved in Canada

Sitagliptin Canadian Product Monograph, 2008; FDA. US prescribing information. 2008;FDA. Information for healthcare professionals exenatide. 2008; Garber A, et al. Lancet 2009.

nausea with liraglutide
Nausea with Liraglutide

Proportion of subjects with nausea by week and treatment; safety population1

  • Patient withdrawals due to nausea were infrequent (2-4%)1
  • In a separate study, the average patient rating of gastrointestinal adverse event severity was a maximum of 2 on a seven-point scale2
  • Garber A, et al. Lancet 2009
  • Horowitz M, et al. Diabetes Obes Metab. 2008;10(7):593-6.

Liraglutide is not yet available in Canada

non significant weight reduction with sitagliptin added to patients uncontrolled on metformin
Non-significant Weight Reduction with Sitagliptin added to Patients Uncontrolled on Metformin

Body Weight

0.0

-0.2

(n = 86)

(n = 77)

LS mean change from baseline

-0.4

p = 0.954 vs placebo

-0.6

Sitagliptin 100 mg

Placebo

-0.8

0

6

12

18

Weeks

Excluding data after initiation of glycemic rescue

Raz I, et al. Curr Med Res 2008;24:537

sustained weight reduction over 52 weeks with liraglutide
Sustained Weight Reduction Over 52 Weeks With Liraglutide
  • Waist circumference was reduced from baseline by 3.0 cm with liraglutide 1.8 mg
  • Waist circumference increased by 0.4 cm with glimepiride (p< 0.0001)

*

*

Glimepiride 4 mg/day

Liraglutide 1.2 mg/day

Liraglutide 1.8 mg/day

*p< 0.0001 for change from baseline

Garber A, et al. Lancet 2008 Sep 24 [Epub]

liraglutide improves cell function
Liraglutide Improves β-cell Function

Baseline

56.4%

70.6%

45.5%

56.3%

0.48

0.45

0.42

0.45

p= 0.0313

p= 0.0033

Change in proinsulin:insulin

HOMA (%)

Liraglutide

1.8 mg

Liraglutide

1.2 mg

Rosi-glitazone

Placebo

Liraglutide

1.8 mg

Liraglutide

1.2 mg

Rosi-glitazone

Placebo

Mean ± 2SE

Study NN2211-1436

Marre, et al. Diabetes 2008;57(suppl 1):A4

glp 1 agonists versus dpp 4 inhibitors
GLP-1 Agonists versus DPP-4 Inhibitors

*Not yet approved in Canada, + Blonde et al. Poster presented at CDA 2008

liraglutide

Liraglutide

Victoza

liraglutide indications canada
Liraglutide Indications - Canada

Once-daily administration for the treatment of adults with type 2 diabetes to improve glycemic control in combination with:

Metformin, when diet and exercise plus maximal tolerated dose of metformin do not achieve adequate glycemic control

Metformin and a sulfonylurea, when diet and exercise plus dual therapy with metformin and a sulfonylurea do not achieve adequate glycemic control

Liraglutide should not be used in type 1 diabetes, pregnancy and pediatric population

Victoza Product Monograph, Novo Nordisk Canada Inc., 2010.

rosiglitazone
Rosiglitazone
  • CHMP (Committee of the European regulatory agency): All rosiglitazone-containing medicines should be suspended across the EU – the benefit of Rosiglitazone do not outweigh its risks
  • In US – all rosiglitazone containing medicine will remain available with additional safety labelling and restrictions of use. FDA requires a risk evaluation programme.
rosiglitazone42
Rosiglitazone
  • Canada – rosiglitazone will be available, with the same safety labelling and restrictions
  • GSK – will not promote rosiglitazone in any country including Canada
  • Pioglitazone will continue to be available with no change in its status compare to previous
type 2 diabetes oha
Type 2 Diabetes - OHA
  • Start with Metformin if no contraindications
  • Avoid early use of SU
  • DDP4 inhibitors and GLP1 analogs can be used as second line of therapy
  • pioglitazone and acarbose are other options
  • Insulin should be used at any point in the therapy if glucose targets are not met
type 2 dm insulin45
Type 2 DM - Insulin
  • Role for insulin early in disease
    • Beta cell glucose toxicity
    • Relieve symptoms rapidly
  • Failure of combination of oral agents
  • Contraindication to oral agents
      • Renal failure
      • Dropping CrCl.
types of insulin
Types of insulin
  • Bolus (meal):
    • Rapid acting – Humalog, Novorapid, Apidra
    • Short acting – Regular or Toronto
  • Basal:
    • Lantus, Levemir
    • Novolin NPH, Humulin N
  • Pre- mix:
    • Analog mix - NovoMix 30Humalog Mix 25 & Humalog Mix 50
    • Regular mix - 30/70, 40/60, 50/50,
fitting the insulin regimen to the patient
BG Pattern

Diet

Lifestyle

Insulin

Fitting the Insulin Regimen to thePatient

High fasting, with minimal glucose rise throughout day

Small regular meals

-MDI reluctant -Needs orals

Basal-Only Insulin

Premixed QD or BID

Any fasting glucose, with glucose rises during the day

Large suppers & small lunches

-MDI reluctant -Consistent daily routine

Any glucose pattern

Match any diet

-Erratic schedule -Motivated to achieve tight control

Basal Bolus [MDI]

Adapted from Hirsch I. Clinical Diabetes 2005; 23(2):78-86

slide48
The Relative Contribution of Glucose control as one strives for a better A1c3*

FPG

PPG

30%

50%

60%

55%

70%

Contribution (%)

70%

50%

45%

40%

30%

<7.3 7.3 to 8.4 8.5 to 9.2 9.3 to 10.2 >10.2

A1c Range (%)

* 290 non-insulin and non-acrabose- using patients with type 2 diabetes for at least 6 months. Plasma glucose concentrations were determined at fasting (8:00 AM) and postprandial and post absorptive (11:00 AM, 2:00 PM and 5:00 PM).

3. Adapted from Monnier L, et al. Diabetes Care. 2003;26:881-885.

the insight trial
The INSIGHT Trial
  • A 24-week, randomized, open-label, parallel-group study conducted at 19 specialist sites and 34 sites led by family physicians.
  • Patients were randomized to receive either insulin glargine added to their current oral therapy with an insulin self-titration protocol (n=206) or physician-managed intensification of oral glucose-lowering therapy with no added insulin (n=199).
  • Patients in the OADs-only group were conventionally managed by their physicians.

Gerstein HC, et al. Diabet Med 2006;23(7):736–42.

results
Results
  • Patients receiving glargine achieved greater glycemic control than those on OADs only:
    • 1.68 times more likely to achieve two consecutive AIC 6.5%
    • Achieved lower FPG
    • Reported greater treatment satisfaction
    • No difference in the rate of hypoglycemia

Gerstein HC, et al. Diabet Med 2006;23(7):736–42.

basal insulin
Basal Insulin
  • Addition to oral agents
  • Can continue with all OHA including
    • Metformin, SU
  • Stop: TZD, DPP4 inhibitors
  • Titration is needed from the onset in this regimen
    • Increase by 2 units every 2 days until fasting is at target (ie <7 )
once daily titration schedule cda guidelines
Once-daily titration schedule:CDA guidelines

Canadian Diabetes Association. Can J Diabetes 2008;32(Suppl 1):S1–201.

switch from nph once daily to long acting insulin analogue once daily
Switch from NPH once daily to long-acting insulin analogue once daily

Canadian Diabetes Association. Can J Diabetes 2008;32(Suppl 1):S1–201.

Lantus Product Monograph, 2008.

Levemir Product Monograph, 2005.

patient not at target with basal insulin

Patient Not at Target with Basal Insulin

Move on to twice daily PreMix or Multiple Daily Injections

premix insulin
Premix Insulin
  • Choose analog Premix insulin
    • Humalog Mix 25
    • NovoMix 30
  • Advantages:
    • Improves post-prandial control
    • Less nocturnal hypoglycemia
    • Patient’s convenience – can be taken with meal or soon after a meal (no need to take this insulin 30 minutes before meals)
three step approach
Three step approach
  • 1>>>> Get Fasting to Target (<7)
  • 2>>>> Get ac meals to Target (5-7)
  • 3>>>> Get pc meals to Target (<9)
  • **>>>> Always eliminate lows (<4)
summary
Summary

Type 2 diabetes is marked by progressive β-cell dysfunction and insulin resistance

Goal of Therapy in Type 2 diabetes is to slow the progression of the disease and to prevent complications

Avoid SU early in the course of therapy for Type 2 diabetes

summary58
Summary

Incretin based therapy has a role early in treatment of Type 2 diabetes

Insulin plays an important role both early and late in the disease

Patient self-management plays an important role in reaching our goals in managing diabetes

self management training programs diabetes
Self management Training Programs - Diabetes
  • Workshops – 6 weeks
  • www.healthylifeworkshop.ca
  • 1-866-971-5545
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