therapies in the treatment of type ii diabetes...•git hormones secreted from the entero-endocrine...

Therapies in the treatment of Type II diabetesDr. S.A. Bhana

Chris Hani Baragwanath Academic Hospital; University of the Witwatersrand

Type 2 diabetes prevalence by region

Amos et al. 1997

Africa

Asia

North America

Latin America

0 10 20 30 40

Type 2 diabetes prevalence (millions)

50 60 70

Europe

Oceania

Growth of Type 2 diabetes

Amos et al. 1997

Africa

Asia

North America

Latin America

0 20 40 60 80

Increase in Type 2 diabetes prevalence 1997–2010 (%)

100 120

Europe

Oceania

Insulin Resistance: An Inherent Metabolic Abnormality of Type 2 Diabetes and CVD

Increased Free Fatty

Acids

Increased Glucose

Production

Visceral Obesity

Atherosclerosis

Insulin Resistance

Hyperinsulinemia

Type 2 Diabetes

Inflammation (CRP)

Endothelial Dysfunction

Hypertension

Impaired Fibrinolysis (PAI-1)

Dyslipidemia(HDL, sdLDL, TG)

EnvironmentGenes

UKPDS: ß-Cell Function for Patients Remaining on Diet for 6 Years

Adapted from UKPDS Group (UKPDS 16). Diabetes. 1995;44:1249-1258.

0

20

40

60

80

100

-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6

Years After Diagnosis

-C

ell F

unction (

%

)

N=376

Ins

ulin

Se

cre

tio

n

AIR

(µ

U/m

L)

IGT

NGT

NGTNGT NGT

DIA

500

400

300

200

100

0

Insulin Sensitivity

M-low (mg/kg EMBS per minute)

Progressors

Non-Progressors

Early Insulin Secretion DecreasesWith Progression to Diabetes

Weyer C, et al. J Clin Invest. 1999;104:787–794.

1 2 3 4 5

Case scenario 1• 44 year old female with features of

metabolic syndrome. (HTN, BMI =40)

• Currently on Metformin 850mg TDS and HbA1c is >10%.

• What other information would you need prior to escalating therapy?

• What is the next best step in terms of her therapy?

T2DM treatment strategies revisited

Target-driven therapy*

Adapted from Riddle M. Endo Metab Clin NA 1997;26:659―77.

Riddle M. Am J Med 2004;116:35―95.*Individualise

STEP 1

STEP 2

STEP 4

OHA monotherapy

OHA combinations

STEP 3

Lifestyle modification

Basal insulin

Basal plus prandial

SEMDSA 2012 Algorithm

Case scenario 2

• 38 year old T2DM presents with established renal failure requiring dialysis and proliferative retinopathy. Her treatment includes Metformin 850mg TDS and Sulphonylurea 80mg BD. HbA1C is 8%

• What would you do next?

SGLT2 inhibitors

Metformin

Introduction

• T2DM is a poorly managed disease with fewer than 50% of pts achieving glycaemic targets.

• A uniform therapeutic approach will not be appropriate for a disease that presents with great diversity in pts

• Ideally we need to match these diverse profiles with various therapeutic options whilst still maintaining a systematic and logical approach

Optimal management

• Ongoing patient education

• Lifestyle intervention at each step

• Control glycaemia (pre- and post-prandial)• Avoidance of hypoglycemia

• Avoidance of weight gain

• Individualize therapy

• Control all CVS risk factors

Hypoglycemia

Weight gain

CVS risk

Decrease compliance

Microvascularcomplications

Challenges

Complications in Type 2 diabetes

Turner et al. 1996

01

10

20

30

40

Pa

tie

nts

wit

h e

ve

nt

(%) All diabetes-related events

Macrovascular complications

2 3 4 5 6 7 98

Time from randomisation (years)

0

Microvascular complications

Lifestyle measures

• Diet

• Weight loss

• Stop smoking

• Ongoing counseling

Goals of therapy

•HbA1C < 7%, higher if underlying CVS risk

•Glucose pre-prandial: 4-7 mmol/L

•Glucose post-prandial 4-8mmol/L

•Prevention of target organ damage

Good Glycaemic Control Reduces Incidence of Complications: Data From Landmark Trials

HbA1C

DCCT1

9%7%

Kumamot

9%7%UKPDS

3

9%7%

Retinopathy (%) 63 69 21

Nephropathy (%) 54 70 34

Neuropathy (%) 60 – –

Macrovascular disease (%) 41 – 16

The Ominous Octet

Islet -cell

Impaired

Insulin Secretion

Neurotransmitter

Dysfunction

Decreased Glucose

Uptake

Islet a-cell

Increased

Glucagon Secretion

IncreasedLipolysis

Increased Glucose

Reabsorption

Increased

HGP

DecreasedIncretin Effect

SulfonylureasGlinidesInsulin

Incretins

MetforminTZD

SGLT2 inhibitors

Metformin

MetforminInsulins

Incretins

GLP 1 analoguesAmylin mimmetics

‘OMINOUS OCTET’

Special considerations in drug selection

• Age

• Weight

• Comorbidities

• Hypoglycemia prone

• Impaired cardiac, renal and liver function

Comparison of 24-hour glucose levels in control subjects vs patients with diabetes (p<0.001).

Adapted from Polonsky K, et al. N Engl J Med 1988;318:1231―9.

Time of day (hours)

400

300

200

100

0

6 610 14 18 22 2

Pla

sma g

lucose

(m

g/dl)

Normal

Meal Meal Meal

20

15

10

5

0

Pla

sma g

lucose

(mm

ol/

l)

Treating fasting hyperglycaemia lowers the entire 24-hour plasma glucose profile

Hyperglycaemia due to an increase in fasting glucose

T2DM

Oral agents

Classes of oral agents

• Biguinides- Metformin

• Sulphonylureas- Gliclazide, Glibenclamide

• PPAR γ agonists- Rosiglitazone

• α glucosidase inhibitors- acarbose

• Glinides- nateglinide

• DPP4 inhibitors- ‘gliptins’

• SGLT2 inhibitors- Canagliflozin

Injectables

Injectables

• GLP 1 analogues- Exenatide, Liraglutide

• Insulins• Short acting

• Intermediate acting

• Long acting

• Ultra-long acting

Step 1:

First lineMetformin monotherapy

Advantages Disadvantages

Low cost GIT side effects

HbA1C 1.5% Limited durability

Low risk hypoglycemia

Modest weight loss

Step 2:

Met

form

in Sulphonylureas

Incretin

Basal insulin

Sulfonylureas


Low cost Hypoglycemia

Long clinical experience Limited durability

HbA1C 1-2% Weight gain

Possible CVS risk

Incretins

• GIT hormones secreted from the entero-endocrine cells

• GIP and GLP-1

• Action: potentiates insulin secretion (glucose dependent)

• Delays gastric emptying

• Satiety

• Degraded by DPP-4 enzyme

Incretins

DPP4 inhibitors

•‘gliptins’

GLP1 analogues

•Liraglutide and exenatide

DPP4 inhibitors GLP 1 analogues

Effect on HbA1C HbA1c 0.5-1% HbA1c 1%

Advantages Weight neutral Weight loss

Low risk hypoglycemia No hypoglycemia

Improves post prandial control

Improves pre- and post-prandial glucose

Disadvantages Some cases ofpancreatitis

Some cases ofpancreatitis

safety dataNo Harm

? Medullary Ca

safety data“Leader” Better then Std.

Injectable

Step 3:

• SU

• Basal insulinMetformin

• SU

• IncretinMetformin

• SU

• Acarbose/SGLT 2Metformin

Normal renal glucose handling1–3

SGLT, sodium-glucose co-transporter. 1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10–18; 2. Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35; 3. Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14–21.

SGLT2

Glucose

Majority of glucose is

reabsorbed by SGLT2

(90%)

Proximal tubule

Remaining glucose is reabsorbed by SGLT1

(10%)

Minimal to no

glucose excretion

Glucose

filtration

SGLT2 inhibitor

Proximal tubule

Glucose

filtration

SGLT2 inhibitors selectively inhibits SGLT2 in the renal proximal tubule1

SGLT2

Glucose

SGLT2 INH.

SGLT2

Increased urinary glucose excretion

Mechanism of Action of SGLT2 Inhibitors

Inhibition of SGLT2 Reversal of glucotoxicity

Insulin sensitivity in muscle• ↑ GLUT4 translocation• ↑ Insulin signaling• Other

Insulin sensitivity in liver• ↓ Glucose- 6-phosphatase

Gluconeogenesis• Decreased Cori cycle• ↓ PEP carboxykinase

-Cell function

EMPA-REG OUTCOME CVOT overview

• High CV risk patients T2D (MI, stroke, CAD, UA, PAD); A1c 7-10%

Results:• Age ca. 64 yrs• BMI = 30 kg/m2• CV risk = 99%• HbA1c = 8%• T2D = >10 yrs

Primary endpoint: time to 1st occurrence of any of the following adjudicated components of the primary composite endpoint (3P-MACE)

1. CV death (including fatal stroke and fatal MI)

2. Non-fatal MI (excluding silent MI)

3. Non-fatal stroke

CV death

42

HR 0.62(95% CI 0.49, 0.77)

p<0.0001

Cumulative incidence function. HR, hazard ratio

0.5 1.0 2.0

Patients with event/analysedEmpagliflozin Placebo HR (95% CI) p-value

Intent-to-treat population

164/4687 69/2333 1.18 (0.89, 1.56) 0.2567

Fatal and non-fatal stroke

Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; *Excluding events >30 days after last intake of study drug and patients who received study drug for <30 days (cumulative)

On-treatment analysis*

141/4607 66/2308 1.04 (0.78, 1.40) 0.7849

0.5 1.0 2.0

Favoursempagliflozin

Favoursplacebo

Numerical difference largely driven by events occurring >30 days after treatment stop Favours

empagliflozinFavoursplacebo

Patients with event/analysedEmpagliflozin Placebo HR (95% CI) p-value

3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382

CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001

Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189

Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638

4-point MACE 599/4687 333/2333 0.89 (0.78, 1.01)* 0.0795

0.25 0.50 1.00 2.00

3-point MACE and 4-point MACE

44

Favours empagliflozin Favours placebo

Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction

*95.02% CI

Heart failure

45

Hospitalisation for heart failure

46

HR 0.65(95% CI 0.50, 0.85)

p=0.0017

Cumulative incidence function. HR, hazard ratio

All-cause mortality

47

All-cause mortality

48

HR 0.68(95% CI 0.57, 0.82)

p<0.0001

Kaplan-Meier estimate. HR, hazard ratio

Insulins

Basal insulin

Premixed twice daily

Basal bolus


Universally effective Hypoglycemia

Low cost Weight gain

No long term risk of cancer

Injectable

Benefit for micro vascular

complications

Newer Insulins

How to start insulin therapy

Insulin therapy in Type 2 patients on OADs can be started as:

• Supplemental therapy

• Substitution therapy

Dosage: Initial 10 units; titration* to FPG <5.5 mmol/l

(<100 mg/dl) without hypoglycaemia

FPG** mmol/l (mg/dl)

2

8

4

6

Insulin glargine dose

increment* (IU/day)

5.5―6.7 (100―120)

10.0 (180)

6.7―7.8 (120―140)

7.8―10.0 (140―180)

*Increased weekly if no severe hypoglycaemia and no PG <4 mmol/l (<72 mg/dl), using means of most recent FPG values; **over 2―3 days.

Treat-to-Target study: dose titration algorithm

Riddle M, et al. Diabetes Care 2003;26:3080―6.

Forced weekly insulin titration algorithm

LANMET study: treatment algorithm

• Patients self-adjusted dose

• FPG values transferred by modem to diabetes monitoring centre

• Insulin dose titrated to FPG 4.0―5.6 mmol/l (72―100 mg/dl)

Measure FPG daily for 3 days

If mean of FPG measurements

>5.6 mmol/l (>100 mg/dl)

ADD 2 UNITS OF BASAL INSULIN

FPG=fasting plasma glucose.

Yki-Jarvinen H, et al. Diabetes 2004;53(suppl 2). Abstract 2181-PO.

No increase in dose if FPG <4.0 mmol/l (<72 mg/dl)

LANMET study: similar HbA1c reduction achieved in both treatment groups

Study end

Bedtime NPH vs insulin glargine, plus metformin 2 g

NS=not significant.


5

6

7

5.7

FPG

(m

mol/

l)

NS

6

8

9

7

10

HbA

1c

(%)

Baseline

7.1

6.0

9.5

NPH insulin

Insulin glargine

All patients

Study end

7.1

LANMET study: significantly less hypoglycaemia with insulin glargine

NPH insulin

Insulin glargine

20

60

80

40

100

70

0

68

Insulin dose

(units/day)

1

3

4

2

5

3.5

2.6

NS

Weight gain

(kg)

0

Symptomatic

hypoglycaemia

(events/patientyear)

2

6

8

4

10

8.0

5.5

0

NS

―44%

Bedtime NPH vs insulin glargine, plus metformin 2 g

p<0.05

NS=not significant.


AT.LANTUS: no difference in the incidence of severe hypoglycaemia between clinic- and patient-driven titration algorithms

Incid

ence o

f hypogly

caem

ia (

%)

Hypoglycaemia

Severe

(<50 mg/dl)

Symptomatic Nocturnal

0.9 1.1

26.3

29.7

3.24.1

0.2 (90%CI ―0.3,

0.7)

NS

3.4 (90%CI 1.2, 5.5)

Significant

0.9 (90%CI 0.0, 1.9)

NS

30

25

20

15

10

5

0

Clinic-driven algorithm

Patient-driven algorithm

Davies M, et al. Diabetes Care 2005;28:1282―8.

AT.LANTUS: significantly greater reduction in HbA1c achieved with patient- than with clinic-driven titration algorithms

Clinic-driven

algorithm (n=2,315)

Patient-driven

algorithm (n=2,273)

―1.08

―1.22

p<0.001

HbA

1c

(%)

0

―0.25

―0.50

―0.75

―1.00

―1.25


AT.LANTUS study: summary

• Simple insulin titration • A simple patient-driven titration algorithm significantly

improved glycaemic control

• No increase in severe hypoglycaemia compared with a clinic-driven algorithm

• Keys to success• Self-monitored blood glucose

• Self-adjustment of insulin dose


24-hours.

The confidence of steady basal insulin release –

all day and all night.

Multiple-daily injections (1,4)

“Insulin glargine as the basal insulin combined with rapid-

acting insulin

analogues (insulin lispro, insulin aspart) is probably the most

physiological insulin substitution therapy available by

subcutaneous injection and will therefore be the basis for

future comparisons” (3)Sources: 1.Leahy JL. Insulin Therapy. New York, NY: Marcel Dekker Inc, 2002. 2.Bolli GB. Diabetalogia 1999; 42:1151-1167. 3.Owens DR, Zinman B, Bolli GB.

Insulins today and beyond. The Lancet 2001;358(9283)739-746.

A Review of Different Therapies…

Intermediate-acting insulins: NPH

• Does not mimic basal insulin profile(1,2)

— Variable absorption

— Pronounced peak

— 13-16 hour duration

— Requires twice-daily administration to provide 24-hour

basal insulin coverage

• Fear of hypoglycaemia(3)

— Major factor limiting insulin adjustmentsMultiple-daily injections (1,4)

Source: 1.Leahy JL. Insulin Therapy. New York, NY: Marcel Dekker Inc, 2002. 2. Chan JL, Mayo Clin Proc 2003;78:459-467. 3. Bergenstal RM, Endocrinology, 4th ed. Philadelphia,

PA: WB Saunders Co,: 2001:821-835. 4.Bolli GB. Diabetalogia 1999; 42:1151-1167.

Pre-Mixed Insulin regimens (1,2)

• Inadequate insulin coverage

• Poor long-term control

• Failure to match endogenous secretion pattern

• Dawn phenomenon

• Increased glycaemia

Twice-daily split-mixed regimens(1,2)

A Review of Different Therapies

Source: 1.Leahy JL. Insulin Therapy. New York, NY: Marcel Dekker Inc, 2002. 2.Bolli GB. Diabetalogia 1999; 42:1151-1167.

CVS risk modification

• Stop smoking

• BP control

• Aspirin (primary and secondary prevention)

• Lipid lowering agents (primary and secondary prevention)

Hypertension and diabetes-

therapy related benefits

Reduction in risk of complications in tight (144/82 mm Hg)

versus lower (154/87mm Hg) BP control

- 32%

- 24%

- 44%

- 56%

- 37%

UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713.

Hypertension and diabetes

Death related to

diabetes

Complications related to diabetes

Stroke

Heart failure

Microvascular complications

Goals of BP lowering

• All stages (watch ISH & low DBP) <140/90

• Diabetes mellitus <130/85

• Renal insuff (Cr >220 umol/L) <130/85

• Proteinuria<125/75

• Congestive heart failure <120/80

Number of Antihypertensive Agents Needed to Achieve Target Blood Pressure

Adapted from Bakris GL, et al. Am J Kidney Dis 2000; 36: 646–61

ALLHAT (138 mm Hg)

IDNT (138 mm Hg)

RENAAL (141 mm Hg)

UKPDS (144 mm Hg)

ABCD (132 mm Hg)

MDRD (132 mm Hg)

HOT (138 mm Hg)

AASK (128 mm Hg)

Average Number of Antihypertensive Agents/Patient

1 2 3

Trial/SBP Achieved

Total Cholesterol

LDL Cholesterol

Triglycerides

HDL Cholesterol

5

3

1.5

1.2

mmol/L

mmol/L

mmol/L

mmol/L

New SA Lipid Targets

S Afr Med J 2000;90:164-178

Turner RC, Br Med J 1998;316:823-8

Dyslipidaemia

Hypertension

Hyperglycaemia

Cigarette Smoking

LDL > 3.9 mmol/L

SBP > 142 mmHg

HBA >7.5%

current

1

Upper ThirdCut-off Point

HazardRatio

RiskFactor

2.26

1.82

1.52

1.41

Independent Risk Factors for Coronary Heart Disease in the UKPDS

0.5

1

1.5

2

2.5

3

Sm

okin

g

Micro

alb

um

inuria

Mal

e Gen

der

Tot

al C

hole

ster

ol

Sys

tolic BP

Rela

tive R

isk

MICROALBUMINURIA COMPARED TO TRADITIONAL RISK FACTORS FOR ISCHAEMIC HEART DISEASE

N=2,085; 10 year follow-up

Borch-Johnsen K, et al.

Arterioscler Thromb Vasc Biol. 1999;19(8):1992-1997.

Diabetic Nephropathy

• Diabetic nephropathy is irreversible in humans

• No case of recovery or cure has been reported in the literature

• Once the clinical signs of nephropathy have become manifest, the natural course is inexorable progressive to death

• The rate of progression is accelerated in the later stages

Kussman et al. JAMA 1976; 236:1861

Morbidity and Mortality Along the Renal Continuum

Risk Factors

Diabetes

Hypertension

Endothelial

Dysfunction

Micro-

Albuminuria

Macro-

ProteinuriaNephrotic

Proteinuria,

End-Stage

Renal Disease

Death

Adapted from Burgess

RENAAL

IDNTIRMA-2

MARVAL

OPTIMISING RENAL PROTECTION

Nephro-protection starts with prevention of proteinuria

Pro-Active Re-Active

Duration of diabetes (years)

UAE µ/min <20 20-200 >200

Normoalbuminuria Micro Macro ESRD

0 13 18 25

BENEDICT RENAALLosartan

IDNTIrbesartan

IRMA 2 Irbesartan

MICRO-HOPERamipril

CKD & CVD screening ?

IN SUMMARY……..

Step 4:

REFER SPECIALIST

Questions

WHO vs ADA Diagnostic Criteria

ADA

-No previous diagnosis of Diabetes

• FPG > 7mmol/l

For IFG

• FPG > 6.1 < 7mmol/l

WHO (1980-85)

For Undiagnosed Diabetes

• FPG > 7 mmol/l OR

2-h postprandial PG >11.1mmol/l

For IGT

• 2-h postprandial PG > 7.8 and < 11.1 mmol/l

Elevated LDL-cholesterol

Low HDL-cholesterol

Elevated systolic BP

Elevated glycated HB

Smoking

Risk Factors for CHD in the UKPDS

Principles of T2DM treatment

‘Treat to Target’ — to predefined goals

‘Stepwise Treatment’ — for a progressive disorder, add

and avoid switching if possible

Optimise and individualise

treatment

American Association of Clinical Endocrinologists. Endocr Pract 2002;8(suppl 1):43―84.

American Diabetes Association. Diabetes Care 2004;27(suppl 1):S15―35.


International Diabetes Federation. Diabet Med 1999;16:716―30.

Japan Diabetes Society. Available at: http://www.jds.or.jp.




Treat-to-Target study: less nocturnal hypoglycaemia with insulin glargine

*p<0.05; **p<0.03; §p<0.005.

HbA1c 7% 57

Dose (units/day)

33 27*

NPH

(n=389)

Insulin glargine

(n=367)

Patients reaching glycaemic targets (%)

FPG <5.5 mmol/l

(<100 mg/dl)

22 16**

58

47.2 41.8§

36 34

without nocturnal

hypoglycaemia

without nocturnal

hypoglycaemia

Treat-to-Target study: summary

• Validated the concept that adding basal insulin

(NPH or insulin glargine) to OHAs in T2DM

restores HbA1c values to target levels in most

patients

• ~60% reached target HbA1c level <7%


Insulin initiation: substitution therapy

Stop OAD treatment

Start 2 injections of 0.2 IU/kg Long acting Insulin or premixed insulin 30/70; 2/3 of the total dose before breakfast and

1/3 before dinner

Dose to be increased by 2-4 IU every 3-4 days,if necessary

If blood glucose levels are too high after meals,premixed insulin is a better choice than long-acting Insulin

Human Insulins and Insulin Analogues

•The time course of action of any insulin can vary in different people or at different times in the same person. For this reason, time periods indicated here should only be considered general guidelines.

Insulin Preparations Onset of Action Peak of Action (h) Duration of Action (h)

Rapid-acting

Regular human insulin1 30 to 60 minutes 2 to 4 6 to 8

Insulin glulisine 5 to 15 minutes2 1 to 23 3 to 44

Insulin lispro/aspart1 5 to 15 minutes 1 to 2 3 to 4

Intermediate-acting

NPH1 1 to 3 h 5 to 7 13 to 16

Lente1 1 to 3 h 4 to 8 13 to 20

Detemir5,6,7 — 4 to 6 20 h

Long-acting

Insulin glargine1 1 to 2 h No Peak 24 h

Ultralente1 2 to 4 h 8 to 14 <20 h

Premix

Insulin NPL/lispro 75/258 10 minutes 1 to 4 10 to 20

Insulin aspart 70/309 10 minutes 1 to 4 16 to 20

Physiologic Insulin Secretion: 24-hour Profile

Source: Advances in Insulin Therapy: The New Paradigm in Diabetes Care – Martin J Abrahamson (www.Medscape.com CME Activity 27 Sept 2001)

http://www.medscape.com/

Insulin initiation: supplemental therapy

Continue OAD treatment

Add 0.2 IU/kg Insulin at breakfast or at bedtime

Dose to be increased by 2-4 IU every 3-4 days, if necessary

If more than 30-36 IU of insulin is necessary to obtain good metabolic control, consider stopping OAD treatment and continue on insulin alone

Divide the dose into 2 daily injections:

2/3 before breakfast

1/3 at bedtime

When does the patients blood glucose start to go up?• Hyperglycemia develops only when the beta cells fail

• insufficient insulin secretion to overcome insulin resistance

• defective pattern and timing of insulin secretion

• glucose toxicity - sustained hyperglycemia increases insulin resistance and decreases glucose stimulated insulin secretion

100

60

40

20

0

80

-30 0 30 -30 0 30

Time (min)

Control(n=18)

Type 2 diabetes(n=15)

IRI(mU/mL)

Acute Insulin Response to Glucose

Robertson RP, Porte D Jr. J Clin Invest. 1973;52:870-876

Glycaemic control and riskof complications

A Desktop Guide to Type 2 Diabetes Mellitus, European Diabetes Policy Group 1999

Fasting/preprandial Postprandial HbA1c

blood glucose blood glucose (%)(mmol/l)* (mmol/l)*

Low risk < 5.5 < 7.5 < 6.5

Arterial risk > 5.5 > 7.5 > 6.5

Microvascular risk > 6.0 > 9.0 > 7.5

The level of HbA1c alone may be misleading

Service FJ et al. Diabetes Care 1980

Blo

od g

luco

se

Time

HbA1c = 7.5%

Patient 2

Patient 1

Glucose spikes

50% of Type 2 Diabetes Patients Have Complications at the Time of Diagnosis

Retinopathy,

glaucoma or

cataracts

Nephropathy

Neuropathy

MICROVASCULAR MACROVASCULAR

Cerebrovascular

disease

Coronary

heart

disease

Peripheral

vascular

disease

UK Prospective Diabetes Study Group. UKPDS 33. Lancet 1998; 352: 837–853

Metabolic control and macrovascular mortality

Standl et al. 1996

0

10

20

30

Ma

cro

va

sc

ula

r m

ort

ali

ty (

%)

40

< 6.9 % 6.9–8.8 % > 8.8 %

HbA1c

without macrovascular

disease

with macrovascular

disease

Metabolic control and mortality

Gall et al. 1995

0

10

20

Inc

ide

nc

e o

f a

ll-c

au

se

mo

rta

lity

(%

/5 y

ea

rs)

30

> 21 < 21

Urinary albumin excretion rate (mg/24h)

< 7.8

> 7.8

5

15

25

0

0.5

1

1.5

2

2.5

1990 2000 2010

0

200

400

600

800

1000

1200

1981-1990 1991-2000 2001-2010

GLOBAL MAINTENANCE TEN YEAR MEDICAL COSTS

DIALYSIS POPULATION

Lysaght. J Am Soc Nephrol., 2002

$ (

bil

lio

ns

)

mil

lio

ns

PROTEINURIA AND MORTALITY IN PIMA INDIANS

WITH TYPE 2 DIABETES

Nelson et al. Diabetes, 1988

Ag

e-

an

d s

ex

-ad

juste

d

death

s (

x 1

000 p

ers

on

-

year)

Healthy

subjects

Non

proteinuric

diabetics

Proteinuric

diabetics

97% of the excess mortality reported in diabetics is associated with overt proteinuria

30-34

35-39

40-44

45-49

50-54

55-59

60-64

65-69

70-74

<4.1

4.2-5.2

5.3-6.2

6.3-7.2

>7.2

<0.91

0.91-1.16

1.17-1.29

1.3-1.55

>1.55

<120/80

120-129/80-84

130-139/85-89

140-159/90-99

>160/100

Smoker

Diabetic

Age (years)

ScoreWomen

ScoreMen

RISK FACTORS

TC (mmol/L)

HDLC (mmol/L)

BP (mmHg)

-9

-4

0

3

6

7

8

8

8

-2

0

1

1

3

5

2

1

0

-3

-3

0

0

2

3

2

4

-1

0

1

2

3

4

5

6

7

-3

0

1

2

3

2

1

0

0

-2

0

0

1

2

3

2

2

-2

-1

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

1

2

2

2

3

3

4

4

5

6

7

8

10

11

13

15

18

20

24

>27

0

2

3

3

4

5

7

8

10

13

16

20

25

31

37

45

>53

>53

>53

>53

Score Women Men

RISK PERCENTAGE

DR

UG

TH

ER

AP

YIN

DIC

AT

ED

Obesity

Family History

Sedentary Lifestyle

These risk factors should also be taken into consideration

ADD UP RISK SCORES TO OBTAIN RISK PERCENTAGE

10 year risk calculation for

myocardial infarction in

primary prevention

Wilson PWF, et al. Circulation

1998;97:1837-1847

therapies in the treatment of type ii diabetes...•git hormones secreted from the entero-endocrine...

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