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
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1921 Banting and Best
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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
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Spectrum of glucose homeostasis and DM
Source Harrison 18E
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Physiology of glucose metabolism
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Regulation of insulin secretion
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Phases of insulin secretion
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Insulin tissue level
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Pathophysiology of DM
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Signs and symptoms

• Polyurea osmotic diuresis
• Polydypsia
• Weight loss catabolic state
• Fatigue
• Weakness
• Frequent superficial infections
• Blurred vision
• Look for complications

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Physical examination
Weight / BMI Injection sites
Retinal examination Vibratory sensation
Foot examination Tooth examination
Orthostatic blood pressure Peripheral pulses
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Diagnosis
Symptom of DM RBS (Random Blood Sugar) gt 200mg/dl
FBG (Fasting Blood Glucose) gt 126mg/dl
HbA1C (glycosylated Hb) gt 6.5
PPG (OGTT 75 gm anhydrous glucose) gt 200mg/dl
ADA- American Diabetic Association
PPG post prandial glucose
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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

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Chronic Complications of DM
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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.)

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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
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Treatment goals for diabetic adults
Glucemic control
A1c lt 7.0
Pre-prandial capillary plasma glucose 70-130mg/dl
Peak post prandial plasma glucose lt180mg/dl
BP lt130/80
Lipids (LDL) lt100mg/dl
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Comprehensive diabetes care
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Interlocking ideas
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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

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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

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What are the types of insulin regimens?

• Premixed regimen
• Split mix regimen
• Basal bolus regime (multidose)
• Bedtime dosing alone (detemir/Glargine)
• Infusion

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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

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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.

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Management of type 1 DM
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Insulin dosage

• 0.5-1unit/kg per day in divided doses
• 50 - basal insulin
• Insulin sensitive to heat and O2

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Insulin regimes
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Cont
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cont
B breakfast L Lunch S Supper HS night NPH
Neutral protein hagedon
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CSII
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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

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Diabetic ketoacidosis

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

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Point to remember

• DKA
• Always treat in emergency/ICU setting in
  initially 24-48 hours.

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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

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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

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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

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Type 2 DM
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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

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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
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Drug options

• Sulfonylureas
• Meglitinides
• Metformin
• Thiazolidinediones
• a- glucosidase inhibitors
• Peptide analogues
• DPP4 inhibitors
• Insulin

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Different site actions of OHAs
AGI, Pramlinitide
Incretins , SU, Meglitnides
TZD
Metformin
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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
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Hba1c Fbs ppbs
Life style modifications monotherapy
Hba1c Fbs ppbs
Life style modifications
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• Mono therapy
• Dual therapy
• Triple therapy

Met DPP4/ GLP 1, TZD, Glinide/SU
TZD DPP4/GLP 1
Met Colesevalam, AGI
Met GLP 1 or DPP4 TZD
SU or glinide
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Monotherapy for HbA1c 6-7.5

• Metformin (insulin sensitizer) 1st choice
• Except,
• Renal disease
• Hepatic disease
• GI intolerance
• Lactic acidosis
• Secretogogues not preferred

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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

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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

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• 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)

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Triple therapy

• 6 options available
• Metformin 1st agent unless CI
• Exenetide 2nd agent ( or DPP4 inh.)
• Exenetide CI ( pancreatitis)
• 3rd agent glinides/TZD/SU

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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)

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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

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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

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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

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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)

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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

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Combination therapy

• Same dose as monotherapy
• Different M/A So additive
• Eg. SU and Metformin
• Insulin TZD more chances of hypoglycemia,
  weight gain

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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

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Pharmacological agents

• Bigunides - Metformin, phenformin
• Most commonly used drug
• M/A AMP Protein kinase
• HGP ?, peripheral utilization
• 500mg -1000mg bd/day

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Mechanism of action
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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

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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

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

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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.

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Insulin secretogogues
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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
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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

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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.

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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

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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

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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
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Doses
Metformin 0.5-2.5gm 2-3 doses/day
Glimipiride 1-6mg 1
Pioglitazone 15-45 mg 1
Nateglinide 180-480mg 3-4 doses/day
Exenetide (SC) 10-20µg 2 doses/day
Sitagliptin 100mg 1
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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

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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)

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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.

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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.

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Recent advances
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Cont

• Oral insulin physiological insulin
• Use Ecuador ( india biocon )
• Cortisone Cortisol (active)
• Enzyme 11-B hydroxysteroid dehydrogense
• Activators of glucokinase
• Statins pravastatin (most useful)

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Molecular size correlates with rate of absorption
Duration of Action
Molecular size
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Size exclusion chromatography of Degludec in a
subcutaneous model
Multi-hexamer

• After injection, Degludec exists only in the
  multi-hexamer state

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Insulin degludec Mechanism of protraction
Subcutaneous tissue
Multi-hexamers
Monomers
Capillary membrane
Albumin binding
Insulin degludec in blood
Capillary blood
Insulin Receptors
Cell Membrane
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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)

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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

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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)
  

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Summary
INSULIN SECRETAGOGUES KATP SULFONYLUREAS 1st Acetohexamide, Tolbutamide, Chlorpropamide, Tolzamide.
INSULIN SECRETAGOGUES KATP SULFONYLUREAS 2nd Glibenclamide, Glipizide, Gliclazide
INSULIN SECRETAGOGUES KATP SULFONYLUREAS 3rd Glimepiride
INSULIN SECRETAGOGUES KATP MEGLITINIDES/ PHENYLALANINE Nateglinide, Repaglinide
INSULIN SECRETAGOGUES GLP -1 ANALOG Exenatide, Liraglutide Exenatide, Liraglutide
INSULIN SECRETAGOGUES DPP IV INHIBITORS Sitagliptin, Vildagliptin, Saxagliptin Sitagliptin, Vildagliptin, Saxagliptin
INSULIN SENSITIZERS BIGUANIDES Metformin Metformin
INSULIN SENSITIZERS TZD (PPAR) Rosiglitazone, Pioglitazone Rosiglitazone, Pioglitazone
OTHERS a - GLUCOSIDASE INHIBITORS Acarbose, Miglitol, Voglibose Acarbose, Miglitol, Voglibose Acarbose, Miglitol, Voglibose
OTHERS AMYLIN ANALOG Pramlintide Pramlintide Pramlintide
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Thank you