Management Paripurna Diabnetes Mellitus.pptx

Management Paripurna Diabetes Mellitus

Djoko Wahono SoeatmadjiPutu Moda Arsana

Division of Diabetes and Endocrinology, Department of Medicine, Dr Saiful Anwar

Hospital, Medical Faculty, Brawijaya University

PIN PAPDI 2010

TOPICS

• Epidemiology, Classification and Diagnosis• Pathogenic Mechanisms of Type 2 Diabetes

and Pathophysiology of Hyperglycemia• Mangement of Type 2 Diabetes - Therapeutic Guidelines - Therapeutic Life-style Changes - Oral and Parenteral Hypoglycemic Agents - Insulin and Insulin Analogues• Summary and Conclusions

TOPICS



Estimation of IGT Patients in 2003 and 2025

2003 2025

Country Number of Patients (million)

Country Number of Patients (mllion)

India ChinaRusiaUSAIndonesia

85,633,217,813,912,9

ChinaIndiaIndonesiaUSARusia

132,054,320,919,318,3

IDF. Diabetes Atlas 2nd Edition, Executive Summary, IDF 2003

ETIOLOGIC CLASSIFIACTION

I. Type 1 (ß-cell destruction leading to absolut deficiency) A. Immune mediated B. Idiopathic

II. Type 2 • Predominantly insulin resistance + relative insulin deficiency • Predominantly secretory defect + insulin resistance

III. Other specific types

IV. Gestasional diabetes mellitus

ADA. The Expert Committee,1997

Type 1 + Type 2 = 70 – 95% of diabetes

Type 1 Type 2

Clinical Features• Age at onset• Onset• Weight• Spontaneous ketosis• Chronic complicationEpidemiology• Prevalence• SexInsulin (C-petide) levelGenetics • Concordance in twins• HLA asoociationPathology• Islet cell mass• Insulitis at onsetImmunology• Associated with other endocrinopathy• Anti-islet ell immunity Humoral Cell mediatedl

Usually < 30Acute

Non obeseCommon

(++)

0,5%Male

prepdominancece↓↓ / (-)

40%

(+) (DR3/DR4)

Severely reducedPresent

Frequent

60 – 80% at onset35 – 50% at onset

Usually > 40InsidiousObeseRare(++)

2%Female

predominance↓ / N /

70 – 90%(-)

Moderately reduced?

Frequent

5 – 20%< 5%

FAMILY

STUDY

FENOTYPE

VS

GENOTYPE

Disorders of GlycemiaEtiologic types and Stages

Stages Normoglycemia Hyperglycemia

TypesNormal glucoseregulation

IGT or

IFG

Diabetes MellitusInsulin requiring

No For control For survival

Type 1

Type 2

Other types

Gestationaldiabetes

– +++ +++++Insulin requirement

The destruction of ß-cells and the appearance of type 1 diabetes according to the age of onset and the putative pathogenetic mechanism (Paolo Pozzilli and Umberto Di Mario : Diabetes Care 2001 24: 1460-1467)

http://care.diabetesjournals.org/content/vol24/issue8/images/large/dc0814349001.jpeg

Diagnostic Criteria

Screening and Diagnostic Scheme for GDM (24 – 28 week of gestation)

Plasma glucose 50- gscreening test

100- gdiagnostic test

Fasting1- h2- h3- h

-140 mg/dl--

105 mg/dl190 mg/dl165 mg/dl145 mg/dl

The Expert Committee,1997

GDM: Gestational DM

Diagnosis of GDM with a 100-g or 75-g glucose load

mg/dl mmol/l

100-g Glucose loadFasting1-h2-h3-h

75-g Glucose loadFasting1-h 2-h

95180155140

95180155

5.310.08.67.8

5.310.08.6

Two or more of the venous plasma concentrations must be met or exceeded for a positive diagnosis

American Diabetes Association consensus

ADA concensus

Ret

ino

pat

hy

(%)

15

10

5

0

CFPG2hPGHbA1c

42- 87- 90- 93- 94- 96- 101- 104- 109- 120-

34- 75- 86- 94- 102- 112- 120- 133- 154- 195-

3.3 4.9 5.1 5.2 5.4 5.5 5.4 5.7 5.9 6.2

FPG (mg/dl)

2hPG (mg/dl)

HbA1c (%)

Ret

ino

pat

hy

(%) 50

40

30

20

10

0

B

FPG2hPGHbA1c

57- 79- 84- 89- 93- 99- 108- 130- 176- 258-

39- 8- 90- 99- 110- 125- 155- 218- 304- 385-

2.2 4.7 4.9 5.1 5.4 5.6 6.0 6.3 8.5 10.3

FPG (mg/dl)

2hPG (mg/dl)

HbA1c (%)

Ret

ino

pat

hy

(%)

15

10

5

0

A

70- 89- 93- 97- 100- 106- 109- 115- 136- 226-

38- 94- 106- 116- 128- 138- 154- 185- 244- 346-

3.4- 4.8- 5.0- 5.2- 5.3- 5.5- 5.7- 6.0- 6.7- 7.5-

FPG (mg/dl)

2hPG (mg/dl)

HbA1c (%)

FPG2hPGHbA1c

HbA1c target based on risk of microvascular complication

Cumulative hazard curves for ADA fasting glucose criteria and the World Health Organization 2-h glucose criteria

(adjusted by age, sex, and study center)

Follow-up Years

Cummu

l

a

t

I

v

E

Ha

z

a

r

d

s

Fuster F et al, 2008

0 2 4 6 8 10 12

0-2

0-1

0

Feeting glucose classification

Known diabetes

Diabetes by ADA criteria

Impaired fasting glucose

Normal

0 2 4 6 8 10 12

0-2

0-1

0

2 h glucose classification

Known diabetes

Diabetes by ADA criteria

Impaired fasting glucose

Normal

Criteria Diagnosis of Diabetes Mellitus

1. Symptoms (+)

Casual plasma glucose > 200 mg%

(11.1 mmol/L)

or

2. FPG 126 mg% (7.0 mmol/L)

2. During OGTT

2h post 75 g glucose load 200 mg/dl

.

(The Expoert Committee,1997)Fasting at least 8 h

Normal Fasting Normal 2-h Post-gucose Challenge

Diabetes Diabetes

100 mg/dl

99 mg/dl

140 mg/dl

139 mg/dl

126 mg/dl

125 mg/dl200 mg/dl

199 mg/dl

Microangiopathy Risk Macroangiopathy Risk

Garber AJ et al, 2008

Impaired Fasting Glucose(IFG)

Impaired Glucose Tolerance (IGT)

Increased Risk of Micro- and Macroangiopathy Correlates With Progression From Impaired

Glucose Homeostasis to Type 2 DM

Prevention of Disease

Healthy At risk Disease present

Complication (+)

PrimordialPrimary

SecondaryTertiary

Prevention

Prediabetes Diabetes

TOPICS



Pathogenesis of Type 2 Diabetes

Insulin resistance

vs

-cell dysfunction

? ?

Pathogenesis of Type 2 Diabetes

Impaired -Cell function

Enzymatic defects

Reduced mass

Premature aging

Insulin resistance Obesity (Genetic ?)

Inactivity

Hyperglycemia

Hyperinsulinemia

Drugs

Genetic Environmental

Sine qua none (and sufficients )

Secondary and facilitative

Insulin Resistance

Normal -cells

Compensatory Hyperinsulinemia

Isulin Resistance Syndrome

Abnormal -cells

Inadequate Insulin Response

Type 2 Diabetes

CVDHypertension

Dyslipidemia Obesity

Retinopathy Neuropathy Nephropaty

Therapies Address Islet DysfunctionTherapies Address Islet Dysfunction

Islet DysfunctionIslet Dysfunction

Inadequate glucagon

suppression(-cell

dysfunction)

Progressivedecline of β-cell function

Insufficient Insulin

secretion (β-cell

dysfunction)

Sulfonylureas

Glinides

TZDs

Ins. Resistance (Impaired insulin action)

Ins. Resistance (Impaired insulin action)

Adapted from DeFronzo RA. Br J Diabetes Vasc Dis 2003;3(suppl 1):S24–S40

TZDs

Metformin Incretin-basedIncretin-based

Defects in Type 2 diabetesDefects in Type 2 diabetes

Insulin

Pathophysiology of Hyperglycemia

The Physiological Requirement for Insulin

Pancreatic output : basal prandial

• Basal insulin : the amount of insulin necessary to prevent fasting gluconeogenesis (fasting hyperglycemia) and ketogenesis • Prandial insulin : the amaount of insulin necessary to cover meals without development of posprandial hyperglycemia

Mean ( SEM) rates of Insulin Secretion in Type 2 Diabetic Patients compared with Control Subjects

Pathophysiology Hyperglycemia in Type 2 Diabetes

Prandial HyperglycemiaFasting Hyperglycemia

Basal Insulin deficiency

Prandial Insulin deficiency

Treatment Based on the Pathophysiology of Hyperglycemia


Insulin basal Long-acting SU

Metformin

Glitazone

Insulin prandial Short-acting SU Glinide Glitazones

Acarbose

Incretin –based

TOPICS



Physician-coordinatedTeam of Professionals

• physicians• nurse practitioners

• dietitians• pharmacists• mental health

Expertise and a specialinterest in diabetes

Valuations of Therapeutic Goals

By professionals Qualtity of Life By patients

3

2

1

1

2

3

Quality of Life

Perspective in Life(Secondary and tertiary

prevention)

Expectation of Life

Dreyer,1997

Oral Oral+Insulin Insulin

Stages of Type 2 diabetes in Relationship to -cell Function

Type 2 Diabetes is A Progressive Disease:

Lifestyle

The Paradigm of (Type 2) Diabetes Treatment

• Aggressive Treatment – Driven by Target (AIC < 7%)

• Early Combinations - Oral agent – oral agent - Oral agent – insulin • Agressive Insulin Treatment

Less-stringent A1C goals

• History of severe hypoglycemia• Limited life expectancy• Advanced microvascular or

macrovascular complications• Extensive comorbid conditions • Longstanding diabetes

ADA 2009

Type 2 diabetes mellitus (T2DM) requires progressive therapy

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

• When glycaemic targets are not met:

– Treatment should be changed to the next ‘step’

• An ideal treatment strategy 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.

Therapeutic Guidelines

• Individualised• Suited to local data and realities• For the benefit of Indonesia patient

At diagnosis:Lifestyle + Metformin

Lifestyle + Metformin+ Basal insulin

Lifestyle + Metformin+ Sulfonylurea

Lifestyle + Metformin

+ Intensive insulinBasal plus/Basal

bolus

Tier 1:well-validated therapies

STEP 1 STEP 2 STEP 3

Call to action if HbA1c is 7%

Tier 2:Less well validated therapies

Lifestyle + Metformin+ PioglitazoneNo hypoglycaemiaOedema/CHFBone loss

Lifestyle + Metformin+ Pioglitazone+ Sulfonylurea

Lifestyle + metformin+ Basal insulin

Lifestyle + metformin+ GLP-1 agonistNo hypoglycaemiaWeight lossNausea/vomiting

Nathan DM, et al. Diabetes Care 2009;32 193-203.

ADA/EASD consensus algorithm

TOPICS



Medical Nutrition Therapy

• Moderate weight loss (7% body weight)• Dietary fiber (14 g fiber/1,000 kcal) and

foods containing whole grains• Monitoring carbohydrate intake (glycemic

index/glycemic load, carb-counting or experienced-based estimation)

• Saturated fat intake should be 7% of total calories and reducing intake of trans fat

Individualised !!!

Moderate-intense Exercise

At least 30- 60 minutes 4x/week or 150 minutes/week

AerobicRessistance training 3x/week

(if no contraindication)

TOPICS




Lifestyle + Metformin+ Basal insulin

Lifestyle + Metformin+ Sulfonylurea

Lifestyle + Metformin

+ Intensive insulinBasal plus/Basal

bolus




Tier 2:Less well validated therapies

Lifestyle + Metformin+ PioglitazoneNo hypoglycaemiaOedema/CHFBone loss

Lifestyle + Metformin+ Pioglitazone+ Sulfonylurea

Lifestyle + metformin+ Basal insulin

Lifestyle + metformin+ GLP-1 agonistNo hypoglycaemiaWeight lossNausea/vomiting


ADA/EASD consensus algorithm

The Paradigm of (Type 2) Diabetes Treatment

• Aggressive Treatment – Driven by Target (AIC < 7%)

• Early Combinations - Oral agent – oral agent - Oral agent – insulin • Agressive Insulin Treatment

Any single oral therapy is unlikely to lower A1c > 1.5 %, it is logical to

consider initial combination therapy for

patients presenting with an A1c > 8.5%

Dailey GE. Diabetes Care 2005; 28:220-221Nathan DM et al. Diabetes Care 2006; 29:1963-1972

When to start combination ?

Glucose

Adipose tissue

Gut

Stomach

Liver

Sulphonylureas and Glinides

BiguanidesMuscle

Pancreas

Insulin

a-glucosidase inhibitors

Thiazolidinediones

DPP-4 inhibitors

DPP-4

GLP-1

GLP-1 analogues

Adapted from Kobayashi M. Diabetes Obes Metab 1999; 1(Suppl. 1):S32–S40.Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329.

Pratley RE & Salsali A. Curr Med Res Opin 2007; 23:919–931.Todd JF & Bloom SR. Diabet Med 2007; 24:223–232.

Primary Sites of Action of Anti-diabetic Agents

Anti-hyperglycemic Medications for Type 2 Diabetes Mellitus

Agent Expected HbA1c reduction

InsulinSulphonylureasMetformin-Glucosidase inhibitorsThiazolidinediones (Pioglitazone)GlinidesGLP analoguesAmylin analogues Dipeptidyl peptidase IV (DPP-IV) inhibitors

No limit (theoretically)1 – 2%1 – 2%0.5 – 1.0%1 – 1.5%1 – 2%1%0.4 – 0.6%0.6 – 0.8%

Inzucchi SE and McGuire D. Circulation 2008; 117:574 - 584

Oral Agent Failure Rates

Agent Primary failure rate

Secondary failure rate

Sulfonylurea

Glinide

Biguanides

-Glucosidase inhibitor

Thiazolidinediones

15 – 30%

?

< 10%

Dependent on diet adherence

As high as 25%

5 – 10%/year

?

5 – 10%/year

Unknown

Unknown

Feingloss,1999


and/orSU

Lifestyle + Metformin+ SU + Basal insulin

Lifestyle + Metformin+ Intensive insulin

Basal plus/Basal bolus





ADA/EASD consensus algorithm Modified

TOPICS



The Physiological Requirement for Insulin

Pancreatic output : basal prandial

• Basal insulin : the amount of insulin necessary to prevent fasting gluconeogenesis (fasting hyperglycemia) and ketogenesis • Prandial insulin : the amaount of insulin necessary to cover meals without development of posprandial hyperglycemia

Characteristics of insulin preparation used in physiological insulin regimens

Onset of action

Peak of action

Duration of action (h)

Mealtime (prandial) insulins

Soluble (regular) 30 – 60 (m) 2 – 3 (m) 5 – 8

Rapid-acting analogues (lispro,aspart,glulisine)

5 – 15 (m) ½ – 3 (m) 3 – 5

Basal insulin

Intermediate-acting insulin (e.g. NPH)

30 – 90 (h) 4 – 6 (h) 8 – 16

Long-acting analogGlargineDetemir*

2 – 4 (h) Peakless 20 – 24

Mixture (prandial + basal)Novomix (70/30) 0.5 – 1 (h) Dual 10 - 16

(Skyler, 2005)

Pathophysiology Hyperglycemia in Type 2 Diabetes


Basal Insulin deficiency

Prandial Insulin deficiency

Treatment Based on the Pathophysiology of Hyperglycemia


Insulin basal Long-acting SU

Metformin

Glitazone

Insulin prandial Short-acting SU Glinide Glitazones

Acarbose

Incretin –based


and/orSU

Lifestyle + Metformin+ SU + Basal insulin

Lifestyle + Metformin+ Intensive insulin

Basal plus/Basal bolus





ADA/EASD consensus algorithm Modified

Why targetting basal hyperglycemia first ???

Insulin and Glucose Pattern in Type 2 Diabetes: Basal vs Meal-time

Riddle MC. Diabetes Care 1990;13:676-686

Insulin and Glucose Patterns in Type 2 Diabetes: Basal vs Mealtime

Normal

Type 2 diabetes

Riddle MC. Diabetes Care. 1990. 13:676-686; Riddle MC. Practical Cardiology

250

200

150

100

50

0

0600 1200 1800 2400 0600

Time of day

Pla

sma

glu

cose

(m

g/d

L)

Basal Hyperglycemia Mealtime Hyperglycemia

Insulin After Failure of Oral Agents (A1C > 7%)

• OPTION 1– Continue (1 or 2) oral agents

– Start one injection of NPH or Long-acting

analog insulin at bedtime

• OPTION 2– Stop oral agents

– Start two NPH/Mix or one Long-acting analog

insulin injection regiment

Starting Basal (NPH Insulin or Long-acting Insulin Analogs)

• Start dose around 10 (at bed-time)• Adjust dose by fasting/preprandial (SM)BG• Increase dose (2 – 4 ) every 3 to 5 days

as needed• Treat to target basal (fasting/preprandial

70 - 130 mg%)

Insulin Regimen Consisting of Bedtime Injection of NPH or Long-acting analog + OHA

B L S HS B

INS

UL

IN E

FF

EC

T

MEALS

AMorning

Afternoon

Evening

Night

NPH / LENTELong-acting analog

NPH

Oral Agents

B L S HS B

INS

UL

IN E

FF

EC

T

MEALS

Afternoon

NPH

Insulin Regimen Consisting of 2 Injections/dayof Pre-mixed Insulin

Night

NPH

Morning

Short-/Rapid acting

Evening

REGShort-/Rapid-acting

Multiple-dose Regimen Providing Preprandial Injectionsof Short-/Rapid-acting Insulin before meals

A

B L S HS B

INS

UL

IN E

FF

EC

T

MEALS

Morning

Afternoon

Evening

Short-/Rapid-acting insulin before meal

N Engl J Med 2009;361:1736-47

Changes from baseline to 3years in clycated hemoglobin, fasting plasma glucose, and body weight and the rate of

hypoglycemia

TOPICS



Microvascular complications of diabetes are much more

closely associated with hyperglycemia than with

macrovascular complications

Should the glycaemic target be lowered < 7% ?

The effect of lowering of blood glucose to near normal levels

on cardiovascular risk ?

Results of Past (UKPDS) and Recent (ADVANCE, ACCORD,

VADT) Clinical Trials

Glycemic Control in Type 2 Diabetes: Time for an Evidence-Based About-Face?

Montori VM and Ferna´ ndez-Balsells M. Ann Intern Med Ann Intern Med. 2009;150:803-808

Annals of Internal Medicine

Glycemic Control in Type 2 Diabetes• Early and aggressive treatment for newly diagnosed

(UKPDS/UKPDS after 10 years)• Glycemic control efforts should individualize hemoglobin

A1c targets so that those targets and the actions necessary to achieve them reflect patients’ personal and clinical context and their informed values and preference

• Less stringent glycemic target for certain patients • Tight glycemic control may burdens patients with

complex treatment programs, hypoglycemia, weight gain, and costs and offers uncertain benefits in return

• Clinicians should prioritize supporting well-being and healthy lifestyles, preventive care, and CV risk reduction in these patients

Montori VM and Ferna´ ndez-Balsells M. Ann Intern Med Ann Intern Med. 2009;150:803-808

Old friends (insulin, sulfonylureas and metformin), used

appropriately, are and will be still our best friends….

When the facts change, I change my mind. What

do you do, sir?

John Maynard Keynes

Documents

Management Paripurna Diabnetes Mellitus.pptx