PIN PAPDI 2010

Management Paripurna Diabetes Mellitus

Djoko Wahono Soeatmadji Putu Moda Arsana

Division of Diabetes and Endocrinology, Department of Medicine, Dr Saiful Anwar Hospital, Medical Faculty, Brawijaya University

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
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

Estimation of IGT Patients in 2003 and 2025

2003 Country Number of Patients (million) 85,6 33,2 17,8 13,9 12,9 Country 2025 Number of Patients (mllion) 132,0 54,3 20,9 19,3 18,3

India China Rusia USA Indonesia

China India Indonesia USA Rusia

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

ETIOLOGIC CLASSIFIACTION
I. Type 1 (-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
Type 1 + Type 2 = 70 95% of diabetes ADA. The Expert Committee,1997

Type 1
Clinical Features Age at onset Onset Weight Spontaneous ketosis Chronic complication Epidemiology Prevalence Sex Insulin (C-petide) level Genetics Concordance in twins HLA asoociation Pathology Islet cell mass Insulitis at onset Immunology Associated with other endocrinopathy Anti-islet ell immunity Humoral Cell mediatedl
Usually < 30 Acute Non obese Common (++) 0,5% Male prepdominancece / (-) 40% (+) (DR3/DR4) Severely reduced Present Frequent 60 80% at onset 35 50% at onset

Type 2
Usually > 40 Insidious Obese Rare (++) 2% Female predominance /N/ 70 90% (-) Moderately reduced ? Frequent 5 20% < 5%

F A M I L Y S T U D Y

F E N O T Y P E VS G E N O T Y P E

Disorders of Glycemia Etiologic types and Stages

Stages Normoglycemia
Types
Normal glucose regulation

Hyperglycemia
IGT or
IFG
No

Diabetes Mellitus
Insulin requiring
For control For survival

Type 1 Type 2 Other types Gestational diabetes

Insulin requirement

+++

+++++

The destruction of -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)

Diagnostic Criteria

Screening and Diagnostic Scheme for GDM

(24 28 week of gestation)

Plasma glucose 50-g 100-g screening test diagnostic test
Fasting 1-h 2-h 3-h 140 mg/dl 105 190 165 145 mg/dl mg/dl mg/dl mg/dl

GDM: Gestational DM

The Expert Committee,1997

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

mg/dl
100-g Glucose load Fasting 1-h 2-h 3-h 75-g Glucose load Fasting 1-h 2-h 95 180 155 140

mmol/l
5.3 10.0 8.6 7.8

95 180 155

5.3 10.0 8.6

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

American Diabetes Association consensus

A
Retinopathy (%) 15
10 5

B
Retinopathy (%)

FPG 2hPG HbA1c

50 40 30 20 10

FPG 2hPG HbA1c

0 FPG (mg/dl) 70- 89- 93- 97- 100- 106- 109- 115- 136- 2262hPG (mg/dl) 38- 94- 106- 116- 128- 138- 154- 185- 244- 346HbA1c (%) 3.4- 4.8- 5.0- 5.2- 5.3- 5.5- 5.7- 6.0- 6.7- 7.5-

0 FPG (mg/dl) 57- 79- 84- 89- 93- 99- 108- 130- 176- 2582hPG (mg/dl) 39- 8- 90- 99- 110- 125- 155- 218- 304- 385HbA1c (%) 2.2 4.7 4.9 5.1 5.4 5.6 6.0 6.3 8.5 10.3

C
Retinopathy (%) 15 10 5

FPG 2hPG HbA1c

0 FPG (mg/dl) 422hPG (mg/dl) 34HbA1c (%) 3.3

87- 90- 93- 94- 96- 101- 104- 109- 12075- 86- 94- 102- 112- 120- 133- 154- 1954.9 5.1 5.2 5.4 5.5 5.4 5.7 5.9 6.2

HbA1c target based on risk of microvascular complication

ADA concensus

Cumulative hazard curves for ADA fasting glucose criteria and the World Health Organization 2-h glucose criteria (adjusted by age, sex, and study center)
0-2
Feeting glucose classification
Known diabetes
Diabetes by ADA criteria Impaired fasting glucose Normal

C u m m u l a t I

0-2

2 h glucose classification
Known diabetes
Diabetes by ADA criteria Impaired fasting glucose Normal

0-1

v E

0-1

H a
z a

0 0 2 4 6 8 10 12

r d s

0 0 2 4 6 8 10 12

Follow-up Years

Fuster F et al, 2008

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

Fasting at least 8 h

(The Expoert Committee,1997)

Increased Risk of Micro- and Macroangiopathy Correlates With Progression From Impaired Glucose Homeostasis to Type 2 DM
Microangiopathy Risk
Macroangiopathy Risk

Diabetes 126 mg/dl

125 mg/dl Impaired Fasting Glucose (IFG) 100 mg/dl 99 mg/dl Normal Fasting

Diabetes
200 mg/dl 199 mg/dl Impaired Glucose Tolerance (IGT) 140 mg/dl 139 mg/dl Normal 2-h Post-gucose Challenge
Garber AJ et al, 2008

Prevention of Disease
Prediabetes
Healthy At risk

Diabetes
Disease present

Complication (+)
Primordial
Primary

Secondary Tertiary

Prevention

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

Pathogenesis of Type 2 Diabetes

Insulin resistance
? vs ?

-cell dysfunction

Pathogenesis of Type 2 Diabetes

Impaired -Cell function Enzymatic defects Reduced mass Premature aging Sine qua none (and sufficients ) Insulin resistance
Obesity (Genetic ?) Inactivity Hyperglycemia Hyperinsulinemia Drugs

Secondary and facilitative

Genetic

Environmental

Insulin Resistance
Normal -cells
Compensatory Hyperinsulinemia

Abnormal -cells Inadequate Insulin Response

Isulin Resistance Syndrome

Hypertension Dyslipidemia Obesity

Type 2 Diabetes

CVD

Retinopathy Neuropathy Nephropaty

Therapies Address Islet Dysfunction

Defects in Type 2 diabetes

Ins. Resistance (Impaired insulin action)

Inadequate glucagon suppression (-cell dysfunction)

Islet Dysfunction
Insufficient Insulin secretion (-cell dysfunction) Progressive decline of cell function

TZDs Metformin

Sulfonylureas

TZDs

Incretin-based

Glinides

Insulin
Adapted from DeFronzo RA. Br J Diabetes Vasc Dis 2003;3(suppl 1):S24S40

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

Fasting Hyperglycemia Prandial Hyperglycemia

Basal Insulin deficiency

Prandial Insulin deficiency

Treatment Based on the Pathophysiology of Hyperglycemia

Fasting Hyperglycemia Prandial Hyperglycemia

Insulin basal Long-acting SU Metformin Glitazone

Incretin based

Insulin prandial Short-acting SU Glinide Glitazones Acarbose

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

Physician-coordinated Team of Professionals

physicians nurse practitioners dietitians pharmacists mental health
Expertise and a special interest in diabetes

Valuations of Therapeutic Goals

By professionals Qualtity of Life By patients
1

3
2 1

Quality of Life Perspective in Life

(Secondary and tertiary prevention)

Expectation of Life

Dreyer,1997

Stages of Type 2 diabetes in Relationship to -cell Function

Type 2 Diabetes is A Progressive Disease:
Lifestyle
Oral Oral+Insulin Insulin

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 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: p9951015. 2. Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S215.

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

ADA/EASD consensus algorithm

Call to action if HbA1c is 7%

Tier 1:
well-validated therapies At diagnosis: Lifestyle + Metformin Lifestyle + Metformin + Basal insulin Lifestyle + Metformin + Intensive insulin Basal plus/Basal bolus

Lifestyle + Metformin + Sulfonylurea

STEP 2

STEP 1

STEP 3

Tier 2:
Less well validated therapies Lifestyle + Metformin + Pioglitazone
No hypoglycaemia Oedema/CHF Bone loss

Lifestyle + Metformin + Pioglitazone + Sulfonylurea

Lifestyle + metformin + GLP-1 agonist

No hypoglycaemia Weight loss Nausea/vomiting
Nathan DM, et al. Diabetes Care 2009;32 193-203.

Lifestyle + metformin + Basal insulin

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

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 Aerobic Ressistance training 3x/week (if no contraindication)

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

ADA/EASD consensus algorithm

Call to action if HbA1c is 7%

Tier 1:
well-validated therapies At diagnosis: Lifestyle + Metformin Lifestyle + Metformin + Basal insulin Lifestyle + Metformin + Intensive insulin Basal plus/Basal bolus

Lifestyle + Metformin + Sulfonylurea

STEP 2

STEP 1

STEP 3

Tier 2:
Less well validated therapies Lifestyle + Metformin + Pioglitazone
No hypoglycaemia Oedema/CHF Bone loss

Lifestyle + Metformin + Pioglitazone + Sulfonylurea

Lifestyle + metformin + GLP-1 agonist

No hypoglycaemia Weight loss Nausea/vomiting
Nathan DM, et al. Diabetes Care 2009;32 193-203.

Lifestyle + metformin + Basal insulin

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

When to start combination ?

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

Primary Sites of Action of Anti-diabetic Agents

Muscle
Thiazolidinediones
Biguanides

DPP-4 inhibitors

Adipose tissue

Liver

DPP-4 GLP-1

Pancreas
Insulin
Glucose

Stomach

Gut
GLP-1 analogues
Sulphonylureas and Glinides -glucosidase inhibitors

Adapted from Kobayashi M. Diabetes Obes Metab 1999; 1(Suppl. 1):S32S40. Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309329. Pratley RE & Salsali A. Curr Med Res Opin 2007; 23:919931. Todd JF & Bloom SR. Diabet Med 2007; 24:223232.

Anti-hyperglycemic Medications for Type 2 Diabetes Mellitus

Agent
Insulin Sulphonylureas Metformin -Glucosidase inhibitors Thiazolidinediones (Pioglitazone) Glinides GLP analogues Amylin analogues Dipeptidyl peptidase IV (DPP-IV) inhibitors

Expected HbA1c reduction

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
Sulfonylurea Glinide Biguanides -Glucosidase inhibitor Thiazolidinediones

Primary failure rate

15 30% ? < 10% Dependent on diet adherence As high as 25%

Secondary failure rate

5 10%/year ? 5 10%/year Unknown

Unknown

ADA/EASD consensus algorithm Modified

Tier 1:
well-validated therapies At diagnosis: Lifestyle + Metformin and/or SU
STEP 1

Lifestyle + Metformin + SU + Basal insulin

Lifestyle + Metformin + Intensive insulin Basal plus/Basal bolus

STEP 2

STEP 3

Call to action if HbA1c is 7%

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

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

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 (Skyler, 2005)

Onset of action Mealtime (prandial) insulins Peak of action Duration of action (h)

Soluble (regular)
Rapid-acting analogues (lispro,aspart,glulisine)

30 60 (m)
5 15 (m)

2 3 (m)
3 (m)

5 8
3 5

Basal insulin Intermediate-acting insulin (e.g. NPH) Long-acting analog Glargine Detemir* Mixture (prandial + basal) Novomix (70/30) 30 90 (h) 4 6 (h) 8 16

2 4 (h)

Peakless

20 24

0.5 1 (h)

Dual

10 - 16

Pathophysiology Hyperglycemia in Type 2 Diabetes

Fasting Hyperglycemia Prandial Hyperglycemia

Basal Insulin deficiency

Prandial Insulin deficiency

Treatment Based on the Pathophysiology of Hyperglycemia

Fasting Hyperglycemia Prandial Hyperglycemia

Insulin basal Long-acting SU Metformin Glitazone

Incretin based

Insulin prandial Short-acting SU Glinide Glitazones Acarbose

ADA/EASD consensus algorithm Modified

Tier 1:
well-validated therapies At diagnosis: Lifestyle + Metformin and/or SU
STEP 1

Lifestyle + Metformin + SU + Basal insulin

Lifestyle + Metformin + Intensive insulin Basal plus/Basal bolus

STEP 2

STEP 3

Call to action if HbA1c is 7%

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

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

Basal Hyperglycemia Mealtime Hyperglycemia

250 Plasma glucose (mg/dL) 200 150 100

Type 2 diabetes

50
0 0600 1200 1800 Time of day

Normal

2400

0600

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

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

A INSULIN EFFECT Morning Afternoon Evening Night

Oral Agents

NPH / LENTE Long-acting analog

NPH

S
MEALS

HS

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

INSULIN EFFECT

Morning Afternoon

Evening

Night

Short-/Rapid acting NPH

REG Short-/Rapid-acting NPH

S MEALS

HS

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

A INSULIN EFFECT Morning Afternoon
Short-/Rapid-acting insulin before meal

Evening

HS MEALS

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
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

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
Annals of Internal Medicine

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

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