In 1869 German medical student Pancreas has two distinct group of cells.
Frederick Banting. J j r Macleod. Charles Best. J b Collip.
Indian physician ( charak and sushruta ) mudhumeha
PAUL LANGERHANS 5 1921 Banting and Best 6 (No Transcript) 7 Introduction
Definition
Diabetes mellitus is a group of metabolic disease characterized by hyperglycemia resulting from defect in insulin secretion insulin action or both.
246 million worldwide
Prediabetes great concern
American diabetic association (ADA) Diabetic Care 282005 8 Spectrum of glucose homeostasis and DM Source Harrison 18E 9 (No Transcript) 10 Physiology of glucose metabolism 11 Regulation of insulin secretion 12 (No Transcript) 13 Phases of insulin secretion 14 Insulin tissue level 15 Pathophysiology of DM 16 Signs and symptoms
Polyurea osmotic diuresis
Polydypsia
Weight loss catabolic state
Fatigue
Weakness
Frequent superficial infections
Blurred vision
Look for complications
17 Physical examination 18 Diagnosis ADA- American Diabetic Association PPG post prandial glucose 19 Categorize into types
Type 1
Type 2
Age lt 30 years
Lean body habitus
Autoimmune attack on ß cells or idiopathic
Require insulin as therapy
DKA
Other autoimmune disorders
Age gt30 years
80 obese can be lean
Insulin resistance relative insulin deficiency
OHAs insulin
HHS type 2 DKA prone
Component of metabolic disorder
LADA latent autoimmune diabetes of adult
20 Chronic Complications of DM 21 Laboratory assessment
FBG
PPBG
Glycosylated Hb (HbA1c )
SMBG ( self monitoring of blood glucose)
Lipid level
TFT
Urine for protein
Stress testing (in high risk pt.)
22 Advantages of HbA1C Testing Compared With FPG or 2HPG for the Diagnosis of Diabetes Standardi zed and aligned to the DCCT/UKPDS Better index of overall glycemic exposure and risk for long-term complications Substantially less biologic variability Substantially less pre-analytic instability No need for fasting or timed samples Relatively unaffected by acute perturbations in glucose levels 23 Treatment goals for diabetic adults 24 Comprehensive diabetes care 25 Interlocking ideas 26 Monitoring level of glycemic control
Always treat in emergency/ICU setting in initially 24-48 hours.
41 (No Transcript) 42 Monitor following measures
Assess ppt factor CXR culture USG
Capillary glucose 1-2 hrly
Acid-base status and e - 4 hrly for 24 hr
BP pulse respiration mental status Urine input-output 1-4 hrly
Measure K every 1-2 hourly
Measure PO4
ECG
43 Hyperglycemic hyperosmolar state (HHS)
Elderly person type 2 DM
Several week H/O polyurea weight loss
Hypotension tachycardia altered mental status
Relative insulin deficiency and fluid intake
Glucose 1000mg/dl osmolarity gt350mos/l
Prenatal azotemia
Mortality 15
44 Treatment of HHS
Fluid balance
Start with 0.9 NS 1-3L over 1-3 hr
Fast Repletion of fluid neurological dysfunction
Na gt 150meq/l - 0.45 NS use
Hemodynamic stability 0.5 dextrose use
Glucsoe insulin infusion after glucose 250mg/dl
Insulin same as DKA
45 Type 2 DM 46 Food and exercise
Medical nutrition therapy
Glycemic index ( GI)
150 min/wk (atleast for 3 days)
Type 2 resistance training
Exercise can lead hypo/hyper- glycemia
Pre/inter/after exercise glucose testing
47 The economic driving factors gt Rs. 70/- per kg Rs. 90/- per kg Consumer Price Index shifts favour unhealthy products Adam Drewnowski and SE Specter. Poverty obesity and diet costs. Am J Clin Nutr 2004796 16 48 Drug options
Sulfonylureas
Meglitinides
Metformin
Thiazolidinediones
a- glucosidase inhibitors
Peptide analogues
DPP4 inhibitors
Insulin
49 Different site actions of OHAs AGI Pramlinitide Incretins SU Meglitnides TZD Metformin 50 Pharmacotherapy of type 2 DM
LIFE STYLE MODIFICATION
A1c 7.5 - 9 A1c 6.5-7.5 A1c gt9 Drug naïve Under treatment Monotherapy Met/ TZD/DPP4 inh./AGI Symptom free Symptom nt Dual therapy Triple therapy Insulin /insulin agonist Insulin / insulin agonist No response after at least 2-3 months therapy 51 Hba1c Fbs ppbs Life style modifications monotherapy Hba1c Fbs ppbs Life style modifications 52
Mono therapy
Dual therapy
Triple therapy
53 Monotherapy for HbA1c 6-7.5
Metformin (insulin sensitizer) 1st choice
Except
Renal disease
Hepatic disease
GI intolerance
Lactic acidosis
Secretogogues not preferred
54
Cont
TZD take time to act remains for long time associated with bone fractures
Use metabolic syndrome NAFLD
Proceed to next step after max. dose for adequate duration
55 Dual therapy
Metformin preferred for 1st line for dual therapy
TZD after metformin preferred ( central drug for combination)
Met gt TZD
Incretin mimetic gt DPP4 inh. gt Glinides gt SU
GLP-1 analogue meal induced glucose excursion weight loss
56
Glinides more helpful in meal induced glucose ( HbA1c 7.5)
Standard dual therapy met TZD
Other regime
Metformin colesevalam
(safe LDL es)
Metformin AGI
(anti- atherosclerotic actions)
57 Triple therapy
6 options available
Metformin 1st agent unless CI
Exenetide 2nd agent ( or DPP4 inh.)
Exenetide CI ( pancreatitis)
3rd agent glinides/TZD/SU
58 Insulin
Reason no b cell reserve
Can be combined with OHAs
Most useful metformin
Can be with TZD ( CHF)
3 regime
Basal insulin ( glargine )
Pre mixed insulin ( 2 injections )
Basal bolus (4 injections)
59 HbA1c 7.5-9
Start with dual therapy
Metformin 1st agent
Combinations
Metformin GLP1 analogue
Metformin DPP4 inh.
Metformin TZD ( wt. gain edema)
Metformin SU ( more glucose lowering action require)
Metformin glinides
60 Triple therapy
Same as above category
Differences
No use of glinides AGI colesevalam
Metformin TZD SU weight gain edema hypoglycemia
Insulin same as above
Discontinue 1 OHAs
Incretins insulin NOT APPROVED
61 HbA1c gt9
Triple therapy
Insulin should give drug naïve patients
SU give importance
Faster action
Robust Glucose lowering effect
Insulin gradually discontinue after HbA1clt6.5
Give dual/triple therapy
62 Insulin in type 2 DM
DM not controlled with max. dose (metformin 2500mg/day)
Physiological stress infection
Use of parentral nutrition/high caloric diet
DKA/HHS
Gestational DM
CRF
Progressive complication (D. retinopathy)
63 Selection of drugs
Level of hyperglycemia choice of initial therapy
Mild moderate DM (200-250 mg/dl) often respond to monotherapy
More rapid glucose control glucose toxicity
Fast control AGI and Insulin secretogogues
No single agent distinct advantage
TZD target basic problem in type 2
Cost effective metformin SU
64 Combination therapy
Same dose as monotherapy
Different M/A So additive
Eg. SU and Metformin
Insulin TZD more chances of hypoglycemia weight gain
65 CIs of combination therapy
Complicated DM
DM with sepsis
DM with tissue hypoxia and systemic BP less then 90 mm of Hg
Type 1 DM
DKA
DM with pregnancy
Auto immune DM
66 Pharmacological agents
Bigunides - Metformin phenformin
Most commonly used drug
M/A AMP Protein kinase
HGP peripheral utilization
500mg -1000mg bd/day
67 Mechanism of action 68 Alpha glucosidase inhibitor
Risk of Angina / MI and of death from cardiovascular causes.
Pioiglitazone
15-45 mg daily.
PPAR a agonist also.
Decreases triglycerides and Increases HDL.
72 Insulin secretogogues 73 Modes of action Glimepiride (SU) Most Sulphonylureas Glimepiride Glimepiride Sulphonylurea Receptor GLUT-4 So What 65kDa Component absent in Cardiovascular System Safer to use in patients with a higher cardiovascular risk 74 Sulfonylurease
Glyburide Glipizide Gliclazide Glimepirid
Acute administration higher insulin level
Chronic administration before treatment insulin level
Initiated - 5 µg BD and up titrated to 10 µg BD. (S/C)
Weight loss
ADR Nausea diarrhea dizziness headache.
Rarely - acute abdominal pain associated with vomiting. Characteristic of acute pancreatitis.
LAR once weekly regimen dose
0.8 -2 mg
82 Liraglutide
Attach to albumin and thereby acquire pharmacokinetic profile of albumin
Ability to form micellar like aggregates in the subcutis.
Longer half life.
Once daily regimen (S/C)
83 Sitagliptin
DPP 4 Inhibitor
100 mg OD
50 mg if Creatinine clearance 30-50 ml/min
25 mg if Creatinine clearance lt30 ml/min
ADR Nasopharyngitis / URTI
Increase in TLC count 200 cells/ µL
Minimal nausea and vomiting
Serious ADR Hypersensitivity reaction.
84 Vildagliptin
Novartis - withdrawn its intent to submit to FDA as of July 2008.
FDA - Additional clinical data including extra evidence that skin lesions and kidney impairment .On animals have not occurred in human trials.
Not approved in US.
Approved in Feb 2008 by European Medicines Agency.
85 Recent advances 86 Cont
Oral insulin physiological insulin
Use Ecuador ( india biocon )
Cortisone Cortisol (active)
Enzyme 11-B hydroxysteroid dehydrogense
Activators of glucokinase
Statins pravastatin (most useful)
87 Molecular size correlates with rate of absorption Duration of Action Molecular size 88 Size exclusion chromatography of Degludec in a subcutaneous model Multi-hexamer
After injection Degludec exists only in the multi-hexamer state
89 Insulin degludec Mechanism of protraction Subcutaneous tissue Multi-hexamers Monomers Capillary membrane Albumin binding Insulin degludec in blood Capillary blood Insulin Receptors Cell Membrane 90 Gestational and other DM
Intensive treatment required
Fetal macrosomia
Insulin only is used
30-60 - chance of type 2 DM
Pediatric DM
More chances hypoglycemia coma
Metformin only approved (10mg/ml)
91 Prediabetes Whats in a Name
Use for IGT and IFG
If 50 chance of DM next 10 years
Forerunners of DM CV risk
Life style modification and metformin
lt60 years of age
BMI gt35kg/m2
Family history
TG HDL
HT
A1c gt 6.0
92 References
Harrison 18th edition
Goodman and gillman. Pharmacological basis of therapeutics. 12th edition
KDT 6th edition
Medicine update 2008. Vol.18
An algorithm for glycemic control. AACE/ACE consensus statement. Endocr Pract. 200915(No. 6)
93 Summary 94 Thank you
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