1

Diabetes MellitusDiabetes Mellitus

Dr Wayne Riback

Senior Medical Advisor

2

Diabetes is an increasing healthcare epidemic throughout the world

Global projections for the number of people with diabetes

(20–79 age group), 2007–2025 (millions)

South and Central America

Africa

Eastern Mediterraneanand Middle East

Europe

North America

South-East Asia

Western Pacific

28.340.5

+43%

16.232.7

+102%

10.418.7

+80%

24.544.5

+81%

53.264.1

+21%

67.099.4

+48%

46.580.3

+73%

IDF. Diabetes Atlas 3rd Edition – 2006

Worldwide:246 million people in 2007

380 million projected for 2025

3

Diabetes prevalence in the Middle East and Africa is high and increasing

Morocco

Algeria Egypt

Tunisia

SaudiArabia

Iran

Pakistan

IsraelLebanon

SouthAfrica Egypt

2007: 10.1% – 4,3572025: 12.2% – 7,650

Pakistan

2007: 8.3% – 6,9292025: 8.5% – 11,538

Iran

2007: 6% – 2,5652025: 8.4% – 5,115

Saudi Arabia

2007: 13.5% – 1,8552025: 15.7% – 3,610

Lebanon

2007: 7.4% – 1672025: 9.1% – 267Algeria

2007: 7.3% – 1,4752025: 8.9% – 2,528

Morocco

2007: 7.1% – 1,3602025: 9.1% – 2,396

Tunisia

2007: 4.8% – 3172025: 6.2% – 535

Israel

2007: 7.8% – 3372030: 8.5% – 495

South Africa

2007: 4.5% – 1,2132025: 4.4% – 1,279IDF. Diabetes Atlas 3rd Edition –

2006

Prevalence rates and numbers of adults with diabetes (1,000s)

4

How is South Africa performing with respect to DM Practices?

Diabetes Action Now Booklet – Adapted from Wild S. Diabetes care 27: 1047-1053; 2004

5

Patients are uncontrolled with respect to HbA1c

South Africa

HbA1c>7%

HbA1c<7%

0

30

100

% o

f p

atie

nts

30.4

69.4

6

Patients uncontrolled with respect to HbA1c

HbA1c>8.4%

HbA1c<7%

HbA1c 7%- 8.4%

% o

f p

atie

nts

0

30

60

100

South Africa

30.4

31.4

38.2

7

Type 2 DM Patients are not adequately screened for complications

Percentage of patients who have never been screened in the last 12 months

CardioVasculardisease

Eye Nerve Kidney DiabeticFootulcer

Lipid

5

15

25

35

45

South Africa

5.8 8.2 5.9 6.9 5.6 3.1

8

Type 2 DM Patients with complications

Percentage of patients who have diabetes complications

CoronaryArtery

disease

Eye Nerve Kidney DiabeticFootulcer

PVD

5

15

25

35

45

South Africa

14

17

19

4

12

8

9

T2 DM: Only few patients have an HbA1c tested every 6 Months

% o

f p

atie

nts

In the last12 months

Every 6 months

Every3 months

10002030405060708090

100

South Africa

99%

41%

2%

10Jonsson B. Diabetologia 2002;45:S5–S12

The burden of diabetes on healthcare systemsThe burden of diabetes on healthcare systems

CODE-2: cost of type 2 diabetes in Europe

Status of diabetes management

Diabetes accounts for between 5% and 10% of any nation’s health budget

Three times the healthcare resources are being spent on treating diabetes complications compared with that spent on controlling diabetes before the onset of complications

11

Pathogenesis of type 2 diabetes mellitus

12

4:00 16:00 20:00 24:00 4:00

Breakfast Lunch Dinner

8:0012:008:00

Time

Pla

sma

insu

lin

Insulin-glucose profile after mealInsulin-glucose profile after meal

13

Type 2 diabetes mellitus (T2DM) requires progressive therapy

T2DM is a progressive disease characterised by increased insulin resistance and decreasing pancreatic β-cell function1

At diagnosis, patients may have already lost approximately 50% of β-cell function2

An ideal treatment regimen for T2DM should provide: Continuity of care as the disease progresses Flexibility to adapt to individual needs

1. Bergenstal RM. In: Textbook of Diabetes Mellitus, 3rd edition: John Wiley & Sons; 2004: p995―1015.

2. Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21–5.

14HOMA=homeostasis model assessmentAdapted from Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21–5.

Decreasing -cell function as part of the progression of T2DM

Normal -cell

function by HOMA (%)

Time (years)

0

20

40

60

80

100

―10 ―8 ―6 ―4 ―2 0 2 4 6

Time of diagnosis?

Pancreatic function~50% of normal

15

Multiple factors may drive progressive decline of b-cell function

-cell(genetic background)

Hyperglycaemia(glucose toxicity)

Proteinglycation

Amyloiddeposition

Insulin resistance

“lipotoxicity”elevated FFA,TG

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Both FBG and PPBG contribute to overall hyperglycaemia

FBG=fasting blood glucose; IGT=impaired glucose tolerance; PPBG=postprandial blood glucose.

Adapted from Bergenstal RM. In: Textbook of Diabetes Mellitus, 3rd edition: John Wiley & Sons; 2004: p995―1015.

19.416.713.911.18.35.52.8

Plasmaglucose (mmol/l)

Years

350300250200150100

50

Insulin level

Insulin resistance250

200

150

100

50

0

Relative-cell

function (%)

FBGPPBG

Plasmaglucose (mg/dl)

Onset of diabetes

Clinicalfeatures

Uncontrolled hyperglycaemia

Risk for diabetes complications with uncontrolled hyperglycaemia

-cell failure

–10–5 0 5 10 15 20 25 30

Obesity IGT T2DM

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Contribution of fasting hyperglycaemia to overall glycaemia increases with worsening diabetes

ADA=American Diabetes Association; OHA=oral hypoglycaemic agent; PG=plasma glucose.Adapted from Monnier L, et al. Diabetes Care 2003;26:881―5.

290 patients with T2DM treated with diet or OHAsBaseline (normal) PG defined as 6.1 mmol/ l (110 mg/ dl) ―threshold defined by ADA as the upper limit of normal PG at fasting or preprandial times

100

0

50

Rela

tive

con

trib

utio

n (%

)

<7.3 7.3―8.4 8.5―9.2 9.3―10.2 >10.2 HbA1c (%) quintiles

70%

30%

Fasting

18Comparison of 24-hour plasma glucose levels in healthy subjects vs patients with diabetes (p<0.001).Adapted from Hirsch I et al Clin Diab 2005;23:78-86

24-hour plasma glucose profile in T2DM and healthy subjects

Time of day (hours)

400

300

200

100

006:00 06:0010:00 14:00 18:00 22:00 02:00

Pla

sma g

luco

se (

mg/d

l)

Healthy subjectsMeal Meal Meal

20

15

10

5

0

Pla

sma g

luco

se (m

mol/l)

T2DM

19

1. ADA. Diabetes Care 2006;29(suppl 1):S4–S42.2. ADA. Diabetes Care 2006;29(suppl 1):S43–8.3. ADA/EASD Consensus Algorithm - Nathan DM, et al. Diabetologia 2006;49:1711–214. AACE. Endocr Pract 2002;8(suppl 1):40–82.5. IDF. Global Guideline for Type 2 Diabetes. Brussels: International Diabetes Federation, 2005.

http://www.idf.org/webdata/docs/IDF%20GGT2D.pdf.

<7.8**1

(<140)

<5.52

(<100)<6.0

(<110)6.0

(110)3.97.2

(70130) FBG, mmol/l(mg/dl)

<8.0**(<145)

7.8**(140)

<10.0**(<180)

PPBG, mmol/l(mg/dl)

<6.56.5<7.0†HbA1c* (%)

IDF5AACE4

ADA/EASD1&3

Normal

<6.01

Guidelines provide HbA1c, FBG and PPBG targets

*DCCT referenced assays: normal range 4–6%; **1–2 hours postprandial; †ADA/EASD guidelines recommend HbA1c levels as close to normal (<6%) as possible without significant hypoglycaemia1,5

AACE=American Association of Clinical Endocrinologists; ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes; IDF=International Diabetes Federation

Targets for Diabetic Patients

SEMSDA

<7.0(<130)

<8.0(<145)

<7.0

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SEMSDA Guidelines 2009

21

22

0

50

100

150

200

250

-10 -5 0 5 10 15 20 25 30

50100150200250300350

Years of Diabetes

Insulin Resistance

Insulin Level

Fasting Glucose

Beta cell dysfunction

Post Meal Glucose

At risk for DM

©2000 International Diabetes Center. All rights reserved

Glu

cose (

mg

/dL)

% o

f N

orm

al Fu

ncti

on

Adapted from: UKPDS 33: Lancet 1998; 352, 837-853 DeFronzo RA. Diabetes. 37:667, 1988. Saltiel J. Diabetes. 45:1661-1669, 1996. Robertson RP. Diabetes. 43:1085, 1994.

Tokuyama Y. Diabetes 44:1447, 1995. Polonsky KS. N Engl J Med 1996;334:777.

Lifestyle changes Insulin

Metformin(insulin sensitisers)

Secretagogue

Risk for diabetes complications

T2DM is a progressive condition

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InsulinInsulin

The most powerful agent we have

to control glucose

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Balancing Good Glycemic Control with a Low Risk Balancing Good Glycemic Control with a Low Risk of Hypoglycemia…of Hypoglycemia…

Hypoglycemia

Glycemic control

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Imagine consulting room on Monday with Imagine consulting room on Monday with the following:the following:

59 years old male working as a financial manager – sedentary work most of the times during the week – works long hours. Over week-ends he enjoys hikingType 2 diabetes diagnosed 12 years agoHe has hypertension, dyslipidaemia.

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Current medication:

Glimepiride 4 mg/day Metformin 1g bd Irbesartan 300

mg/day Rosuvastatin 10

mg/day Disprin CV 1/day

Case study (continued)Case study (continued)

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Body mass index = 30 Waist circumference =

104.5 cm BP = 120/74 mm Hg No diabetes complications

HbA1c = 8.9% FBG of 9-10 mmol/l PPBG up to 15 mmol/l

Case study (continued)Case study (continued)

28

What will be prescribed?What will be prescribed?

More than 200 combinations of insulin and oral agents are possible: Intensified insulin – basal-bolus or MDI Basal-plus Conventional – premix Basal-oral

Basal – Glargine, Detemir, NPH Bolus – Glulisine, Lispro, Aspart, Human

Regular, Premix- Regular or Rapidacting bolus

component Different % combinations

29

0

20

40

60

<7.3 7.3–8.4 8.5–9.2 9.3–10.2 >10.2

Postprandial

Fasting

Rel

ativ

e co

ntr

ibu

tio

n

of

FB

G v

s P

PB

G (

%)

HbA1c (%)

Adapted from Monnier L, et al. Diabetes Care 2003;26:881–5.

Relative contribution of FBG and PPBG to Relative contribution of FBG and PPBG to HbAHbA1c1c

The relative contribution of PPBG is predominant in subjects with moderate diabetes, whereas the contribution of FBG increases as diabetes worsens

30Comparison of 24-hour glucose levels in control subjects versus patients with diabetes (p<0.001).Adapted from Polonsky K, et al. N Engl J Med 1988;318:1231―1239.Copyright © 2007 Massachusetts Medical Society. All rights reserved.

Time of day (hours)

400

300

200

100

006.00 06.0010.00 14.00 18.00 22.00 02.00

Plas

ma

gluc

ose

(mg/

dl)

Normal

Meal Meal Meal

20

15

10

5

0

Plasma glucose (m

mol/l)

Treating fasting hyperglycaemia lowers Treating fasting hyperglycaemia lowers the entire 24-h plasma glucose profilethe entire 24-h plasma glucose profile

Hyperglycaemia due to an increase in fasting glucoseT2DM

32

Case studyCase study

Max OAD HbA1c = 8.9% FBG of 9-10 mmol/l PPBG up to 15 mmol/l Hb

33

More physiologic insulin More physiologic insulin replacement replacement

==Basal – Bolus/ Basal-PlusBasal – Bolus/ Basal-Plus

34

FBG <6mM but HbA1c >7.0% (>6.5%)introduce Glulisine before meal with max BG

excursion >7.8mM (>10mM)

4

8

12

8 1812 22.00 hrs

Glu

cose

(mm

ol/l

)

Breakfast DinnerLunch

0

Snack

glargine

OHAs+

glargine

Metformin no change (2g/d)Glimepiride, gliclazide SR no change, Glibenclamide, gliclazide no change, reduce or stop pre-dinner doseMeglitinides need to stop pre-dinner dose

*Start Glulisine 4 units based on SMBG if PPBG >/=7.8 mM Titrate upwards by 2 units every 5-7 days to achieve PPBG <7.8mM

Glulisine*

Type 2 DMType 2 DM RRx x StrategiesStrategies : ‘Basal-Plus’ : ‘Basal-Plus’ therapytherapy

35

Insulin treatment options in type 2 diabetesInsulin treatment options in type 2 diabetes

Basal insulin therapy

Long-acting insulin

+/- oral agents

Prandial / Intensified

Insulin Therapy

Short acting insulin or rapid insulin analog prandially +

long-acting insulin

ConventionalInsulin Therapy

2-3 injections

mix of regular insulin / rapid-acting insulin analog and long-acting insulin

Basal Plus therapy

long-acting insulin

+ rapid acting analog with 1-2 meals

+/- oral agents

36

Insulins

Class of insulin ProductAction onset

Action duration

Peak/max

Human Insulins

Shortacting ActrapidHumulin R

30 min 8 hrs 2.5-5hrs

Intermediate-acting: Isophane Zinc suspension

Humulin NProtaphaneHumulin L

1.5hr

2.5 hrs

16hrs

20hrs

4-12hrs

7-15hrs

Biphasic/Premixed Actraphane (30/70)Humulin 30/70Mixtard 20/80

30 min 24 hrs 2-12 hrs

Inhaled Insulins Exubera*

Analogue insulins

Ultra shortacting Humalog NovorapidGlulisine*

10-20 min

3-5 hrs 1-3 hrs

Intermediate-acting Detemir 14 hours (hypoglycaemic effect

6-8 hours

Biphasic/premixed Humalog mix 25Novomix 30

10-20 min

15-18 hrs 1-4hrs

Longacting Lantus (Glargine) 1 hr 24 hrs No peak

37

Onset and Duration of Insulin PreparationsOnset and Duration of Insulin Preparations

Gummerson, Irene. Insulin analogues revisited, Hospital Pharmacist, April 2003, vol. 10, p.165 - 172

38

The Ideal Basal Insulin …The Ideal Basal Insulin …

Mimics normal pancreatic basal insulin secretion

Long-lasting effect Smooth peakless profile Reproducible and predictable effects Reduced nocturnal hypoglycemia Once-daily administration for convenience Pharmacodynamic effects similar to insulin

pump

39

Basal/Bolus Treatment Program with Basal/Bolus Treatment Program with Rapid-Acting and Long-Acting AnalogsRapid-Acting and Long-Acting Analogs

Time 4:00 16:00 20:00 24:00 4:00

Breakfast Lunch Dinner

8:0012:008:00

Glargine

Aspartor

Lispro

Aspartor

Lispro

Aspartor

LisproPlasma insulin (U/mL)

75

50

25

0

Verbal communication from Bode, BW. Atlanta, Ga; Feb. 2003.

40

Current Strategies for Improving the Therapeutic Potential of GLP-1

Agents that mimic the actions of GLP-1 (incretin mimetics) DPP-IV–resistant GLP-1 derivatives (dipeptidyl

peptidase) Examples: GLP-1 analogues, albumin bound GLP-1

Novel peptides that mimic some of the glucoregulatory actions of GLP-1 Exenatide- Victoza (NovoNordisk)- Syncria (GSK – Phase II)

Agents that prolong the activity of endogenous GLP-1 DPP-IV Inhibitors

Drucker DJ, et al. Diabetes Care. 2003;26:2929-2940.; Baggio LL, et al. Diabetes. 2004;53:2492-2500.

41

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

42

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

43

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.

Ve

no

us

Pla

sm

a G

luc

os

e (

mm

ol/

L)

Time (min)

C-p

ep

tid

e (

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

**

*

*

**

*

44

The Incretin Effect Is Reduced in Patients With Type 2 Diabetes

0

20

40

60

80

Ins

uli

n (

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 Glucose

Oral Glucose