diabetes management
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Management of Diabetes mellitus
Dr. Kartik Doshi 25.1.2012
Overview
• Learning Objectives
• Introduction
• Disease burden
• Physiology
• Pathogenesis
• Management of type 1 DM
• Management of type 2 DM
• Recent advances
• Summary
• References
Objective
• Types and pathogenesis of DM
• Signs, symptoms and laboratory investigations
• Management of type 1 and type 2 DM
• Recent advances in DM management
• 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”
History
PAUL LANGERHANS
1921 – Banting and Best
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 28:2005
Spectrum of glucose homeostasis and DM
Source :Harrison 18E
Physiology of glucose metabolism
Regulation of insulin secretion
Phases of insulin secretion
Insulin – tissue level
Pathophysiology of DM
Signs and symptoms • Polyurea – osmotic diuresis • Polydypsia• Weight loss – catabolic state• Fatigue • Weakness• Frequent superficial infections• Blurred vision • Look for complications
Physical examination Weight / BMI Injection sites
Retinal examination Vibratory sensation
Foot examination Tooth examination
Orthostatic blood pressure
Peripheral pulses
Diagnosis*Symptom of DM + RBS (Random Blood Sugar)
> 200mg/dl
FBG (Fasting Blood Glucose)
> 126mg/dl
HbA1C (glycosylated Hb) > 6.5%
PPG (OGTT – 75 gm anhydrous glucose)
> 200mg/dl
PPG – post prandial glucose *ADA- American Diabetic Association
Categorize into types
Type 1• Age < 30 years • Lean body habitus • Autoimmune attack on β
cells or idiopathic • Require insulin as therapy• DKA• Other autoimmune
disorders
Type 2• Age >30 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
Laboratory assessment
FBGPPBGGlycosylated Hb (HbA1c )SMBG ( self monitoring of blood glucose) Lipid level TFT Urine for protein Stress testing (in high risk pt.)
Advantages of HbA1C Testing Compared With FPG or 2HPG
for the Diagnosis of Diabetes
Standardized 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
Treatment goals for diabetic adults
Glucemic control
A1c < 7.0%
Pre-prandial capillary plasma glucose
70-130mg/dl
Peak post prandial plasma glucose
<180mg/dl
BP <130/80
Lipids (LDL) <100mg/dl
Comprehensive diabetes care
patient
nutritionist
specialists
DM educator
Endocrinologist
Interlocking ideas
Exercise
Nutrition
Diabetes educatio
n
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 – β hydroxybuterate in blood• Fructosamine assay - hemoglobinopathies
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
What are the types of insulin regimens?
• Premixed regimen
• Split mix regimen
• Basal bolus regime (multidose)
• Bedtime dosing alone (detemir/Glargine)
• Infusion
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”
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.
Insulin dosage
0.5-1unit/kg per day in divided doses
• 50% - basal insulin • Insulin – sensitive to heat and O2
Insulin regimes
Cont…
cont…
B – breakfastL – LunchS –SupperHS – nightNPH – Neutral protein hagedon
CSII
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
Diabetic ketoacidosis
• Diabetic coma • Its an emergency!!!• s/s – nausea, vomitting,
thirst, polyurea• PPt. events• Insulin ↓,glucagon↑↑• Hyperglucemia, ketosis,
acidosis, hyperkelemia, hyponatremia
Point to remember
DKA
Always treat in emergency/ICU setting in initially 24-48 hours.
Confirm diagnosis (plasma glucose, serum ketones, metabolic acidosis)
Assess : serum electrolytes, acid base status, RFT
Replace fluids, 2-3 L of 0.9% saline over 1-3 hrs(15-20ml/kg/hr), 0.45% saline at 250-500ml/hr.
Short acting insulin IV(0.1units/kg) f/b infusion 0.1units/kg/hr, ↑es 2-4hr- no response
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
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 >350mos/l• Prenatal azotemia• Mortality – 15%
Treatment of HHS
• Fluid balance
Start with 0.9% NS 1-3L over 1-3 hr Fast Repletion of fluid – neurological dysfunctionNa > 150meq/l - 0.45% NS useHemodynamic stability – 0.5 % dextrose useGlucsoe – insulin infusion after glucose 250mg/dl Insulin – same as DKA
Type 2 DM
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
The economic driving factors……
Adam Drewnowski and SE Specter. Poverty, obesity, and diet costs. Am J Clin Nutr 2004;79:6 –16
> Rs. 70/- per kg
Rs. 90/- per kg
…Consumer Price Index shifts favour unhealthy products
Drug options
• Sulfonylureas • Meglitinides• Metformin
• Thiazolidinediones• α- glucosidase inhibitors
• Peptide analogues • DPP4 inhibitors
• Insulin
Different site actions of OHAs
AGI,Pramlinitide
Incretins , SU,Meglitnides
MetforminTZD
Pharmacotherapy of type 2 DM
LIFE STYLE MODIFICATION
A1c 6.5-7.5 A1c 7.5 - 9 A1c >9
MonotherapyMet/ TZD/DPP4 inh./AGI
Dual therapy
Triple therapy
Insulin / insulin agonist
Drug naïve Under treatmentSymptom free
Symptom +nt
Insulin /insulin agonist
No response – after at least 2-3 months therapy
• Mono therapy • Dual therapy
• Triple therapy
Met DPP4/ GLP 1, TZD, Glinide/SU
TZD DPP4/GLP 1Met Colesevalam, AGI
Met + GLP 1 or DPP4 TZD
SU or glinide
Monotherapy for HbA1c 6-7.5%
• Metformin (insulin sensitizer) – 1st choice• Except,1. Renal disease2. Hepatic disease3. GI intolerance 4. Lactic acidosis• Secretogogues –not preferred
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
Dual therapy
• Metformin – preferred for 1st line for dual therapy
• TZD – after metformin preferred ( central drug for combination)
• Met > TZD,• Incretin mimetic > DPP4 inh. > Glinides > SU• GLP-1 analogue – meal induced glucose
excursion , weight loss
• 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)
Triple therapy
• 6 options available • Metformin 1st agent unless CI• Exenetide – 2nd agent ( or DPP4 inh.)• Exenetide – CI ( pancreatitis)• 3rd agent – glinides/TZD/SU
Insulin
• Reason – no b cell reserve • Can be combined with OHAs • Most useful – metformin • Can be with TZD ( CHF)• 3 regime 1. Basal insulin ( glargine )2. Pre mixed insulin ( 2 injections )3. Basal + bolus (4 injections)
HbA1c 7.5-9%
• Start with dual therapy• Metformin – 1st agent • Combinations 1. Metformin + GLP1 analogue2. Metformin + DPP4 inh.3. Metformin + TZD ( wt. gain, edema)4. Metformin + SU ( more glucose lowering
action require)5. Metformin + glinides
Triple therapy
• Same as above category • Differences 1. No use of glinides, AGI, colesevalam 2. Metformin +TZD +SU – weight gain, edema,
hypoglycemia• Insulin – same as above • Discontinue ≥1 OHAs• Incretins + insulin – NOT APPROVED
HbA1c >9%
• Triple therapy• Insulin – should give drug naïve patients• SU – give importance Faster actionRobust Glucose lowering effect• Insulin – gradually discontinue after
HbA1c<6.5%• Give dual/triple therapy
Insulin in type 2 DM
DM – not controlled with max. dose (metformin – 2500mg/day)
Physiological stress, infection Use of parentral nutrition/high caloric dietDKA/HHSGestational DMCRFProgressive complication (D. retinopathy)
Selection of drugs
Level of hyperglycemia – choice of initial therapyMild – moderate DM (200-250 mg/dl) – often
respond to monotherapyMore rapid glucose control – glucose toxicity ↓↓Fast control – AGI and Insulin secretogoguesNo single agent – distinct advantageTZD – target basic problem in type 2 Cost effective – metformin, SU
Combination therapy
• Same dose as monotherapy• Different M/A – So additive• Eg. SU and Metformin
• Insulin + TZD – more chances of hypoglycemia, weight gain
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
Pharmacological agents
Bigunides - Metformin, phenformin
Most commonly used drug M/A – AMP Protein kinase
HGP ↓, peripheral utilization
500mg -1000mg bd/day
Mechanism of action
Alpha glucosidase inhibitor
• Acarbose, vogliboseDose – 25 mg evening meal – 50-100mg/every
meal (acarbose)Hypoglycemia – glucose as a treatmentAdditional actions Anti atherosclerotic Anti platelet Decrease fibrinogen, inflammation Cardio protective in IGT patients
Insulin secretogogues
Sulfonylurease
Meglitinide analogues
Glucose , AA
GLP-1 receptor agonist
DPP4 inhibitors
K+K+
140 kDa140 kDa
65 kDa65 kDa
- cell membrane - cell membrane
K+K+
KATP channelKATP channel
Modes of action: Glimepiride (SU) Most Sulphonylureas
Glimepiride
Sulphonylurea
Receptor
65kDa Component absent in Cardiovascular System
Safer to use in patients with a higher cardiovascular risk
So What ??
Glimepiride
GLUT-4
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”
Incretin hormones
GLP-1 receptor agonist• 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
GIP • Secreted K cells• Stimulate – glucose induced• No effect on glucagon • Does not delay gastric
emptying• Circulating level GIP are
normal/high• Same effect• None
GLP – 1 secretion and metabolism
LOWERING OF BLOOD GLUCOSE
INCRETIN GLP -1
DPP – 4 ENZYME INACTIVATES GLP-1
• INHIBITS GLUCAGON
RELEASE
STIMULATES INSULIN
RELEASE
DPP-4 INHIBITORS (DRUGS) BLOCK DPP-4 AND DECREASE
GLUCOSE
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
Recent advances
Cont…
Oral insulin – physiological insulin Use – Ecuador ( india – biocon )
Cortisone Cortisol (active) Enzyme – 11-B hydroxysteroid dehydrogense Activators of glucokinaseStatins – pravastatin (most useful)
Molecular size correlates with rate of absorption
Monomer
Hexamer
Multi-hexamers
Molecular size
Dura
tion o
f A
ctio
n
Di-Hexamer
Capillary membrane
Subcutaneous tissue
Insulin degludec in blood Albumin binding
Monomers
Insulin degludec: Mechanism of protraction
Cell Membrane
Capillary blood
Insulin Receptors
Multi-hexamers
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)
Prediabetes : What’s in a Name?
Use for IGT and IFG If 50% chance of DM – next 10 yearsForerunners of DM, CV riskLife style modification and metformin*
1. <60 years of age2. BMI >35kg/m2
3. Family history4. TG, HDL5. HT6. A1c > 6.0%
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. 2009;15(No. 6)
INSULIN
SECRETAGOGUES K+ATP
SULFONYLUREAS
1st – Acetohexamide, Tolbutamide, Chlorpropamide, Tolzamide.
2nd – Glibenclamide, Glipizide, Gliclazide
3rd – Glimepiride
MEGLITINIDES/ PHENYLALANINE
Nateglinide, Repaglinide
GLP -1 ANALOG
Exenatide, Liraglutide
DPP IV INHIBITORS
Sitagliptin, Vildagliptin, Saxagliptin
SENSITIZERSBIGUANIDES Metformin
TZD (PPAR) Rosiglitazone, Pioglitazone
OTHERSα - GLUCOSIDASE INHIBITORS
Acarbose, Miglitol, Voglibose
AMYLIN ANALOG Pramlintide
Summary
Thank you
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