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