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Transcript of 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
• 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 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)
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
• 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
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
Prandial HyperglycemiaFasting Hyperglycemia
Insulin basal Long-acting SU
Metformin
Glitazone
Insulin prandial Short-acting SU Glinide Glitazones
Acarbose
Incretin –based
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-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
• 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
AerobicRessistance 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
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
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
At diagnosis:Lifestyle + Metformin
and/orSU
Lifestyle + Metformin+ SU + Basal insulin
Lifestyle + Metformin+ Intensive insulin
Basal plus/Basal bolus
Tier 1:well-validated therapies
STEP 1 STEP 2 STEP 3
Call to action if HbA1c is 7%
Nathan DM, et al. Diabetes Care 2009;32 193-203.
ADA/EASD consensus algorithm Modified
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
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
Prandial HyperglycemiaFasting Hyperglycemia
Basal Insulin deficiency
Prandial Insulin deficiency
Treatment Based on the Pathophysiology of Hyperglycemia
Prandial HyperglycemiaFasting Hyperglycemia
Insulin basal Long-acting SU
Metformin
Glitazone
Insulin prandial Short-acting SU Glinide Glitazones
Acarbose
Incretin –based
At diagnosis:Lifestyle + Metformin
and/orSU
Lifestyle + Metformin+ SU + Basal insulin
Lifestyle + Metformin+ Intensive insulin
Basal plus/Basal bolus
Tier 1:well-validated therapies
STEP 1 STEP 2 STEP 3
Call to action if HbA1c is 7%
Nathan DM, et al. Diabetes Care 2009;32 193-203.
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
• 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
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