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Title: management of diabetes mellitus


1
Management of Diabetes mellitus
  • Dr. Kartik
    Doshi
  • 25.1.2012

2
Overview
  • Learning Objectives
  • Introduction
  • Disease burden
  • Physiology
  • Pathogenesis
  • Management of type 1 DM
  • Management of type 2 DM
  • Recent advances
  • Summary
  • References

3
Objective
  • Types and pathogenesis of DM
  • Signs, symptoms and laboratory investigations
  • Management of type 1 and type 2 DM
  • Recent advances in DM management

4
History
  • 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
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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
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10
Physiology of glucose metabolism
11
Regulation of insulin secretion
12
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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
  • Short term SMBG
    complimentary
  • Long term HbA1c
    to each other
  • SMBG
  • 3-4 times/day (pt. taking multiple insulin)
  • Site fingertip
  • CGMS (continuous glucose monitoring system)
  • Ketone bodies ß hydroxybuterate in blood
  • Fructosamine assay - hemoglobinopathies

27
Management Type 1 DM
  • Partially or completely lack insulin
  • INSULIN replacement is essential
  • Basal, exogenous prevent glycogen breakdown,
    gluconeogenesis
  • Meal time glucose uptake and storage

28
What are the types of insulin regimens?
  • Premixed regimen
  • Split mix regimen
  • Basal bolus regime (multidose)
  • Bedtime dosing alone (detemir/Glargine)
  • Infusion

29
Premixed insulin
  • Advantages
  • More accurate dosing
  • Lesser injections
  • Pen devices administer premixed forms
  • Disadvantages
  • Fine tuning may not be possible
  • Strict meal pattern
  • Nocturnal hypoglycemia
  • May need diet changes for insulin rather than
    insulin changes for diet

30
Split-mixed insulin
  • Advantages
  • Less hypoglycemia, with fine tuning
  • More physiologic
  • Adjustable meal pattern
  • Disadvantages
  • More patient education required
  • Cumbersome mixing
  • Pen device not feasible if two injections are
    planned for.

31
Management of type 1 DM
32
Insulin dosage
  • 0.5-1unit/kg per day in divided doses
  • 50 - basal insulin
  • Insulin sensitive to heat and O2

33
Insulin regimes
34

Cont
35

cont
B breakfast L Lunch S Supper HS night NPH
Neutral protein hagedon
36
CSII
37
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38
Hypoglycemic drugs in Type 1 Dm
  • Pramlinitide
  • Amylin analogue, given before meal
  • 15µg start up to 30-60 µg
  • Reduce gastric emptying, Glucagon ?
  • Acarbose
  • Alpha glucosidase inhibitor
  • Reduce absorption of glucose
  • Hypoglycemic reaction Rx Glucose

39
Diabetic ketoacidosis
  • Diabetic coma
  • Its an emergency!!!
  • s/s nausea, vomitting, thirst, polyurea
  • PPt. events
  • Insulin ?,glucagon??
  • Hyperglucemia, ketosis, acidosis, hyperkelemia,
    hyponatremia

40
Point to remember
  • DKA
  • Always treat in emergency/ICU setting in
    initially 24-48 hours.

41
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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
  • Acarbose, voglibose
  • Dose 25 mg evening meal 50-100mg/every meal
    (acarbose)
  • Hypoglycemia glucose as a treatment
  • Additional actions
  • Anti atherosclerotic
  • Anti platelet
  • Decrease fibrinogen, inflammation
  • Cardio protective in IGT patients

69
Thiozolinediiones
  • Pioglitazone, rosiglitazone
  • M/A PPAR ? receptor activator
  • Adipocyte differentiation, hepatic lipid?,
    improve insulin resistance
  • Fatty acid extra adipose to adipose tissue
  • Pioglitazone - safe
  • Troglitazone hepatic failure
  • Rosiglitazone black box warning by FDA

70
  • No hypoglycaemia.
  • C/I - Liver disease, NYHA III and IV.

71
Rosiglitazone
  • 4-8 mg daily.
  • Increases HDL,LDL and Total cholesterol.
  • Decreases FFA.
  • 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
  • 90-99 PPB
  • S/E hypoglycemia (GlyburidegtgtgtGlimipiride)
  • Ischemic preconditioning preserved in
    glimipiride

75
Meglitinide / Phenylalanine analogs
  • Quick and short acting.
  • Useful in elderly and renal impairment.

Repaglinide
  • Peak blood level within 1 hr.
  • Cautious Use in Hepatic impairment.

Nateglinide
  • Few hypoglycemic episodes.

76
Incretins
  • Entero- insular axis / entero-hypothalamo-insular
    axis
  • GIP glucose dependent insulinotropic peptide
  • GLP 1 glucagon like peptide
  • Preserve B cell mass
  • Synthetic incretins use as a drug
  • Incretomimetic and incretin enhancer

77
Incretin hormones
  • GLP-1 receptor agonist
  • GIP
  • Secreted by L cells
  • Stimulate glucose induced
  • Effect on glucagon
  • Delay gastric emptying
  • Circulating level of GLP-1 reduced
  • Enhance B cell proliferation
  • Eg. Exenetide, liraglutide
  • Secreted K cells
  • Stimulate glucose induced
  • No effect on glucagon
  • Does not delay gastric emptying
  • Circulating level GIP are normal/high
  • Same effect
  • None

78
GLP 1 secretion and metabolism
STIMULATES INSULIN RELEASE
INCRETIN GLP -1
LOWERING OF BLOOD GLUCOSE
  • INHIBITS GLUCAGON RELEASE

DPP 4 ENZYME INACTIVATES GLP-1
DPP-4 INHIBITORS (DRUGS) BLOCK DPP-4 AND DECREASE
GLUCOSE
79
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80
Doses
81
Exenatide
  • Synthetic GLP 1 analog
  • Identified - lizard Gila Monster (Heloderma
    suspectum)
  • 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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