Pathophysiology and Disease Staging of Asthma

What Is Asthma?

Reversible, Intermittent, possibly allergic inflammation of the airway which accompanied by wheezing,
cough, chest tightness mostly during the night.
Complex and characterized by variable and recurring symptoms
Caused by:
o Bronchoconstrictionbronchial smooth muscle contraction
o IgE mediated
o Non-IgE mediated (aspirin, exercise, cold air)
o Airway edema
o May or may not be sensed
o Airway hyperreponsiveness
o Airway remodeling
o COPD state
Triad of Asthma: Airflow obstruction, (smooth muscle) bronchial hyperresponsiveness/ hyperplasia,
and inflammation
Types:
o Atopic or extrinsic
o Allergenic asthma, needs to be triggered by allergends
o Non-Atopic or intrinsic
o Viral Infection, Aspirin, exercises, stress, cold, occupations- toxins
NIH Revisions in 2007
Conduct severity rating when/if no long-term control medications are needed
Incorporate number of oral steroid courses needed per year into severity
Go up and down on treatment by "steps" based on level needed to maintain control
o Step 1 (mild) to Step 6
After establishing a step and severity rating, use validated tools to measure control and quality of life
Comorbidities
Prior to/concurrent with assessing severity and starting pharmacologic therapy, must assess for/rule out
comorbidities/complicating factors
If present, must treat

Comorbid/Complicating Factors and Asthma

Obesity
Allergies, Exposure to respiratory irritants
Obstructive sleep apnea (OSA)
Air pollution
Rhinitis/sinusitis
Nonselective beta-blockers
Stress/depression
Sulfites or food allergies
Influenzagive vaccine
ASA/NSAID sensitivity
Other infectionsviral or bacterial
Allergic bronchopulmonary aspergillosis
Occupational exposures
GERD
Goals of Asthma Therapy
To prevent and control asthma symptoms
To improve quality of life
To reduce the frequency and severity of asthma exacerbations
To reverse airflow obstruction
Summary
If patient is off medication: assess severity, then assign step, and from there prescribe medication.
If patient is on medication, work backwards: assign step and severity based on medication.
When patient comes for follow up, assess control and step up or step down.
Constantly assess for, treat, and eliminate comorbidities and complicating factors.
Asthma Classification: The Classic Staging System
Classification by severity "off of meds"
Mild intermittent
o Symptoms
o "Rescue" meds only prn
Mild persistent
o Symptoms >2/week daily, >2/month at night
o Low-dose ICS or alternative
Moderate persistent
o Daily symptoms, but not continuous
o >1 time a week at night
o Typically, on combined ICS+LABA, or, if young child, medium to high dose ICS + Leukotriene
antagonist
Severe persistent
o Continual daily s/s, frequent night symptoms
o In past, typically on daily prednisone
Summary of Asthma Treatment
Step

Sx

Noc Sx

Lung Function

Long term

Quick relief

1 mild intermittent

< 2 wk

2 month

None

SABA (albuterol-INH)

2 Mild persistent

>2wk

>2month

FEV 1 Peak flow

>80%
>80%

SABA (albuterol-INH)

3 & 4 Moderate persistent

5&6 Severe persistent

Daily
Continua
l

>1/wk
Frequent

60-80%
<60%

Inhaled Corticosteroid
and Leukotriene INH (po)
Steroid + LABA
Steroid + LABA + PO
steroids

Advair = fluticasone + salmeterol

Symbicort = budesonide + formoterol
Dulera = mometasone + formoterol

SABA (albuterol-INH)
SABA (albuterol-INH)

Classifying asthma severity in patients after asthma becomes well controlled, by lowest level of treatment
required to maintain control---Need to know

Stepwise Approach: Managing Asthma in Youths 12 Years of Age and Adults

Asthma Acute Care

Acute Asthma: "exacerbation"
Acute or subacute episodes of progressively worsening shortness of breath, cough, wheeze, and chest
tightness (any combination)
Characterized by documentable decreases in expiratory airflow (using PEF or spirometry)
Classified as mild, moderate, severe, or life threatening
Goals of Treating an Acute Exacerbation
Correct hypoxemia using nebulizer
Rapid reversal of airway obstruction
o Repetitive or continuous administration of SABA
Early administration of systemic steroids for moderate/severe exacerbation
Long term Goal
o Reduce likelihood of relapse or recurrence by baseline therapy
To Treat an Acute Exacerbation
Correct hypoxemia
Administer albuterol and ipratropium
After treatmentReassess
Administer oral corticosteroids if needed
Administer adjuvant medications if needed
Assess for infection prior to giving corticosteroids
Quick Relief Medications (Rescue)
Anticholinergics (Atrovent)
Short-acting beta agonists (albuterol)
Systemic corticosteroids
Combined form of Atrovent and albuterol (Duoneb or Combivent)
Quick Relief Medications: Anticholinergics
Ipratropium bromide (Atrovent)
Administer in multiple doses along with SABA in mod/severe exacerbation
Caution if glaucoma or urinary outflow problems
Side effects: dry mouth, constipation, blurred vision, hoarseness, flushing
Short-Acting Beta2-Agonists
First line for acute s/s and prevention of EIB
Albuterol (Proair, Ventolin, Proventil)
Levalbuterol (Xopenex)
Pirbuterol (Maxair)
Relax smooth muscle and increase airflow
Regular use is not recommended
Active portion is R-enantiomer
Albuterol Dosing: Inhaled
0.15 mg/kg/dose; repeat at frequency?
Max 5 mg/dose
Of 0.5% solution 0.010.05 ml/kg/dose (max 1 ml)
0.083% nebulizer solution, premixed
o 1 vial = 2.5 mg albuterol/3 ml NS

= standard adult form

0.63 mg/3 ml NS and 1.25 mg/3ml NS; premixed for smaller children
Albuterol Dosing: Oral
Solution 2mg/5ml
o 26 yo 0.3 mg/kg/day divided TID, max 12 mg/day
o 612 yo 6 mg/24 hr po divided TID, max 24 mg/day
o >12 years and adult 24 mg/dose po TIDQID, max 32 mg/24 hr
o Long-acting form available: VoSpire ER (4 mg and 8 mg)
Albuterol: Safety
Pregnancy category C
Lactation category 1- compatible
No renal or hepatic dosing needed
o

Levalbuterol
R-isomer of racemic albuterol
Side effects = tachycardia, palpitations, tremor, insomnia, nervousness, nausea, headache
As effective as albuterol with fewer cardiac side effects
o Same side effect but use less amount, hence small dose fewer side effects
Dosing not equivalent
o 0.31 to 0.63 mg levalbuterol ~ equal to 2.5 mg of albuterol

Systemic Corticosteroids
Should be used in all moderate to severe exacerbations
Risk of adverse effects related to dose and length of treatment hence the term "steroid burst"
"Steroid burst": short-term (five to seven days), must be tapered off
No consensus on increments or timeline
a. 60/4040/6020/80 0/100
Dosing Memorize
o Prednisone/prednisolone 12 mg/kg/day, max 4080 mg/day outpatient
o COPD 40 mg/day
o Asthma 60 mg/day
Asthma Medications form Leik book
Rescue Medicine
Only one drug class used for rescue: short-acting B2 agonists
Short-acting B2 agonists metered-dose inhalers (MDI) or by nebulizer.
Albuterol (Ventolin HFA) or pirbuterol (Maxair): 2 inhalations q4-6hrs PRN
Levalbuterol (Xopenex HFA): ): 2 inhalations q4-6hrs PRN
Quick onset (15 to 39 minutes) and lasts about 4 to 6 hours.
Used for quick relief of wheezing, but does not treat underlying inflammation
Long-Term Control Medications
These drugs act as anti-inflammatoreis. Must be taken every day to be effective.
Long-acting B2 agonists (LABAs) are not rescue drugs. Must be taken BID
LABAs increase the risk of death from asthma.

Asthma Chronic Care

Medication Classes
o For long-term control of asthma and COPD
o Corticosteroids (inhaled or oral)
o Cromolyn sodium and nedocromil
o Immunomodulators (Xolair)
o Leukotriene modifiers (Singulair)
o Long-acting beta agonists
o Methylxanthines (theophylline)
o Combined meds: ICS + LABA
Inhaled Corticosteroids
Brand names Pulmicort, Flovent, Asmanex, QVAR, Alvesco, Aerobid, etc.
"ICSs are the most potent and consistently effective long-control medication for asthma." (NIH, 2007, p.
216)
Suppress generation of cytokines, recruitment of eosinophils, and release of inflammatory mediators
Less bioavailable than oral steroids so fewer side effects
Known to
o Decrease severity of symptoms
o Increase quality of life
o Increase PEF and spirometry
o Decrease airway hyperresponsiveness
o Prevent exacerbations: fewer oral steroid courses, ER visits, hospitalizations, and deaths
o Attenuate loss of lung function in adults
Decreased Effectiveness
Smokers
Neutrophil predominant inflammation
African American children with poorly controlled asthma
We know that mild to moderate asthmatics do better on ICS than with alternatives
o We also know that with increasing severity, increasing the dose of ICS alone is not enough
ICS Side Effects

Oral thrush: prevent with use of spacer and rinsing after use
o
Monitor for thrush and treat if occurs

Dysphonia: prevent with spacer, rest voice, decrease dose temporarily

Reflex cough/bronchospasm: prevent with slower inhalation or pretreat with SABA

Linear growth velocity: may slow linear growth velocity but uncontrolled asthma may also slow growth
o
Studies show loss in height small, nonprogressive and may be reversible (??).

Bone mineral density: doses >2000 mcg of beclomethasone a day and age >18 years old
o
Consider biphosphonates and monitoring bone density q 12 years if at high risk
o
High-dose inhaled corticosteroids
o
Increased rate of bone fractures with COPD

Disseminated varicella: if only with systemic steroids

o
Prevention: vaccinate!
Thinning of skin/easy bruising
Ocular effects (cataract and glaucoma): no higher risk at low to medium dose
o
Higher risk if + fam hx of glaucoma, need regular eye checks
Hypothalamic-pituitary-adrenal axis function: clinically insignificant or no effect at low or medium dose
o
Some more susceptible
Glucose metabolism: no effect at low doses, some effect at higher dose but still within limits

Dosing Inhaled Steroids in Asthma

How much do you give and at what age?

Oral Steroids: Long-Term Use

Only for the most severe cases
Mechanism: suppresses, controls, and reverses airway inflammation
Side effects closely related to dose, frequency of administration (QOD better than QD), duration of
steroid use
Oral Steroids: Side Effects
Risk of severe varicella
Adrenal suppression
Weight gain/increased appetite
Cushing's syndrome
Most common side effects:
Growth suppression
o Eyes
Dermal thinning
o Adrenals
Hypertension
o Bones
Cataracts and Glaucoma
o Infection
Muscle weakness
Osteoporosis
Striae
Loss of delayed-type hypersensitivity
Decreased IgG

Increased risk for infection

Risk for reactivation of latent TB
Long-Acting Beta Agonists
Salmeterol (Serevent) and formoterol (Foradil)
Active ingredients in Advair, Symbicort, Dulera
MOA: Relax smooth muscle in airway by stimulating Beta-2 receptors, increasing cyclic AMP
antagonizes bronchoconstriction
Used at steps 3,4,5, and 6, combined with inhaled corticosteroids
Lipophilic: stays in lung tissue a long time duration of action for 512 hours
Never use as monotherapy in asthma
May be used as monotherapy in COPD
May be used for prophylaxis of exercise-induced bronchospasm, but frequent/chronic use should
indicate poorly controlled asthma and anti-inflammatory meds started

LABAs: The Issues

Black-box warning
Increase risk of life-threatening or fatal asthma exacerbations associated with regular use of LABA, or
adverse cardiac events
Risk highest in African Americans
Mechanism
o Direct adverse effect on bronchial smooth muscle?
o Maintenance of lung function despite worsening obstruction delay in care?
LABAs: The Newest Research
2012 study done by Wells, etc. (AAAI) showed that patients on ICS + LABA had equal or improved
outcomes to those on ICS alone.
These outcomes were the same in African American patients as other ethnic groups.
Larger and additional studies are needed to continue to observe for adverse outcomes.
LABAs
What is the bottom line in asthma?
o If a patient can be controlled on an inhaled corticosteroid alone, use the inhaled corticosteroid
alone.
o If a patient can not be controlled on an inhaled corticosteroid alone, step up to a LABA+ICS per
NIH guidelines.
o Teach, monitor appropriately.
Combination Medications (ICS + LABA)
Advair = fluticasone + salmeterol
Symbicort = budesonide + formoterol
Dulera = mometasone + formoterol
Advair: start at 4 years old
Symbicort: 5 years old and up
Dulera: age 12 and up
Mainstay of asthma treatment for Step 3 or higher
Preferred therapy for patients group/stage C and D in COPD

Other Preventative Therapies

Cromolyn and Nedocromil
Not preferred but alternative treatment for persistent asthma
Can be used for prophylaxis only effective when admit before the onset of an attack (before mowing
the lawn)
Mechanism: anti-inflammatory
o Cromolyn: Blockade of chloride channels
Modulate mast cell mediator release
o Nedocromil: neutrophils, macrophages, plt, etc.
Modulate eosinophil recruitment
o May protect against hospitalization, lacking data
Cromolyn: Side Effects
Cough
Wheezing
Throat irritation
Dry mouth
Urticaria
Angioedema
Eosinophilic pneumonia
Nedocromil: Side Effects
Cough, bronchospasm
Chest pain
Dizziness
N&V
Diarrhea, abd pain
Dry mouth, bad taste
ALT elevation: liver problems
Pneumonitis with eosinophilia
Immunomodulators
Omalizumab (anti-IgE or Xolair)
o Xolair most common use
Methotrexate
Interleukin-4 receptor
Anti IL-5
Recombinant IL-12
Cyclosporin A
IVIG
Clarithromycin
All "steroid sparing" and to help with long-term control
Omalizumab (Xolair)
Adjunctive therapy in Step 5 or 6 for pts with allergies and severe persistent asthma
Recombinant DNA derived monoclonal antibody to the Fc portion of the IgE antibody
Prevents binding of the IgE to receptor on mast cells on basophils
Causes decrease in release of mediators in response to allergen exposure

Only adjunctive therapy to demonstrate added efficacy to high dose ICS+LABA in patients who
have severe persistent allergic asthma
Approved for patients aged 12 and over known to have inhaled allergen sensitivities
Adverse effects: injection site pain, bruising, urticaria, anaphylaxis, risk of malignancy
Leukotriene Modifiers
Alternative but not preferred treatment for mild persistent asthma
Or adjunct to ICS (12 and over use LABA first)
Leukotrienes: powerful biochemicals released from mast cells, eosinophils, and basophils that
contract smooth muscle, increase vascular permeability, increase mucus secretions, attract
inflammatory cells
Adjuct to inhaled corticosteroids

Leukotriene Inhibitors
5-lipoxygenase pathway inhibitors (Zileuton = Zyflo)
o Approved age 12+
o Need to check LFTs regularly
o Cytochrome P450 inhibitor increase level to Theophyline
o Side effects: headache, nausea, dyspepsia, abd pain
Leukotriene Inhibitors: Side Effects
Vasculitis (rare)
Insomnia
Dream abnormalities
Nausea/vomiting/diarrhea
Elevated liver enzymes
Eosinophilia
Muscle cramps
Cough/rhinorrhea
Leukotriene Receptor Antagonists (LTRAs)
Montelukast (Singulair)
o Can use in children 6 months and older
o Cytochrome P450 substrate
o Benefit of once-daily dosing
Zafirlukast (Accolate)
o Can be used in children 5 years and older
o Cytochrome P450 substrate and inhibitor
o Requires BID dosing
Singulair and Behavior Changes
FDA released alert in 2008
Singulair may increase risk of:
o Mood/behavior changes
o Suicidal thinking/behavior
o Suicide
Cautions all health care providers to review patients on Singulair and assess for behavior changes and
suicidality

Methylxanthines
Theophylline and SR theophylline
Alternative but not preferred treatment for mild persistent asthma and COPD
Alternative but not preferred adjunct to ICS
Provides mild to moderate bronchodilation
Caffeine, in the same family, produces similar effects
Nonselective phosphodiesterase inhibitor
Less effective than ICS, use when pt has aversion to inhaled meds or cost is issue
Methylxanthines: Side Effects
Toxicity an issue: monitor serum levels!
S/S toxicity:
o Severe headache
o Tachycardia, PVCs
o Nausea and vomiting
Many drug interactions
GI upset
GER
Diarrhea
N,v
Abd pain
Nervousness
Insomnia
Muscle cramps
Tremor
Asthma: Long-Term Control Medications
Drug Class
Brand Name
Inhaled Corticosteroid
LABA combination
Leukotriene Inhibitors
Mast Cell stabilizers
Methylxanthines
Immunomodulators

Triamcinolone (Azmacort) BID

Fluticasone (Flovent HFA) BID
Salmeterol (Serevent) BID
Formeterol (Foradil) BID
Salmeterol + Fluticasone (Advair) BID
Montelukast (Singulair) Dialy
Zileuton (Zyflo) Daily
Cromolyn Sodium (Intal) QID
Nadecromil Sodium (Tilade) QID
Theophyline
Omalizumab (anti-IgE) momoclonal
antibody

Side Effects/ Adverse Effects

Oral thrush (gargle after use)
HPA axis suppression, glaucoma
Black box: Increase risk of asthma death
LABAs are not to be used as recue drug
Neuropsychological effects (agitation, aggression,
depression)
Monitor LFTs (Zileuton)
Works better with children
Cough, sneezing
Sympathomimetic. Avoid with seizures,
hypertension, stroke
Several drug interactions
Be equipped and prepared to treat anaphylaxis
when staring this drug

Chronic Obstructive Pulmonary Disease

Definition/Risk for COPD

A progressive decline in lung function, resulting from:

o Normal aging
o Genetics (alpha-1 antitrypsin deficiency)
o Family history of COPD
o Cigarette and marijuana smoking
o Reduced lung growth (prematurity)
o Severe lower respiratory infections prior to age 6
o Asthma (poorly controlled)
o Women (smokers and those exposed to secondhand smoke)
o Teen smokers
o Indoor/outdoor pollutants
o Occupational exposure (organic and inorganic dust, vapors, chemicals)
Definition of COPD
American Thoracic Society (ATS), Global Initiative for Chronic Obstructive Disease (GOLD), NHLBI,
and WHO define COPD as:
o A common preventable and treatable disease, characterized by airflow limitation
o Progressive
o Associated with increased chronic inflammatory response in the airways and lung to noxious
particles or gases
o Influenced by exacerbations, which contribute to the overall severity in individuals
Forms of COPD

Chronic bronchitis: chronic cough for three months in each of two successive years; when other causes
have been ruled out (bronchiectasis).
Emphysema: abnormal and permanent enlargement of airspaces distal to the terminal bronchioles, with
associated destruction of the airspace walls, without fibrosis (however, fibrosis is seen with pneumonia
as well as in the early stages of emphysema).
Asthma: chronic inflammation associated with airway responsiveness, with wheezing, breathlessness,
chest tightness. Airflow obstruction in asthma is usually reversible.

Pathophysiology of COPD
Airway abnormalities in COPD:
Chronic inflammation
Excessive lysis of elastin and other structural proteins in the lung matrix
Protease from neutrophils, macrophages
Elastase
Mononuclear cells
Atrophy (occurring from bronchoconstriction)
Lung parenchyma abnormalities:
Normal structures comprising the acinar include:
Respiratory bronchiole, alveolar ducts, sacs, and alveoli. These structures along with the associated
capillaries, and interstitium form the parenchyma of the lungs.
The part of the acinar affected by permanent dilation or destruction. This helps to name the subtype of
emphysema (proximal acinar; panacinarseen in alpha-1 antitrypsin deficiency; distal acinar).
Pulmonary vasculature:
Changes include intimal hyperplasia
Smooth muscle hypertrophy/hyperplasia, likely due to hypoxic vasoconstriction of small pulmonary
arteries
Destruction of alveoli from emphysema = loss of pulmonary capillary bed
Diagnoses
Be sure of your diagnosis: concurrent dx or differentials
o Asthma
o Bronchiectasis
o Congestive heart failure
o Diffuse panbronchiolitis
o Obliterative bronchiolitis
o Pulmonary hypertension
o Tuberculosis
o Pneumonia
o Pleural effusion
Goals of Management
Relieve symptoms
Improve exercise tolerance
Improve health status
Prevent disease progression
Prevent and treat exacerbations
Reduce mortality
All with minimal side effects of treatment, if possible

Classification of Severity of Airflow Limitation in COPD

(Post-Bronchodilator FEV1)

Subgrouped into A, B, C, and D

o Designations used for prescribing
GOLD 3 and 4 and Groups C and D are more severe, require more medication
Combined Assessment of COPD
Like asthma, COPD has an additional assessment by risk
Low risk: less than or equal to one exacerbation a year and no hospitalizations. GOLD category 1 or 2.
High risk: One or more exacerbations a year or one or more hospitalizations.

Combined Assessment of COPD Chart

Spirometer Parameters
-Green Zone: 80% to 100% of expected volume
Maintain or reduce medications
-Yellow Zone: 50%-80% of expected volume
Maintenance therapy needs to be increased
or patient is having an acute exacerbation.
-Red Zone: Below 50% of expected volume
If after treatment patients PEFR is still
below 50% expected, call 911. If in
respiratory distress, give epinephrine
injection. Call 911
Managing COPD Exacerbations
How do we know it's an exacerbation?
GOLD guidelines define an exacerbation of COPD as
o "an event in the natural course of the disease characterized by a change in the patient's baseline
dyspnea, cough, and/or sputum that is beyond normal day-to-day variations, is acute in onset, and
may warrant a change in regular medication in the patient with underlying COPD." GOLD
(2014) p. 40
Exacerbations
Cardinal symptoms of COPD exacerbation:
o Increase in dyspnea

o Increase in sputum volume

o Increase in sputum purulence

If at least one of these is present, assess for

URI in last 5 days
Fever without apparent cause
Increased wheezing
Increased cough
20% increase in heart rate over baseline

Causes
Infection, CHF, PE
Common organisms: viruses, H. flu, M. catarrhalis, S. pneumonia
Air pollution
Approx. 1/3 of severe exacerbations cannot be identified
Arterial blood gas (in hospital)
EKG
O2 saturation

Assessment of COPD
Assess symptoms
Assess degree of airflow limitation using spirometry
Assess risk of exacerbations

Evaluation
CXR
Pulse oximetry
Management of Exacerbations: Outpatient
Bronchodilators
Oral steroids
Oxygen PRN
Antibiotics
o Patients with exacerbation with two of the cardinal symptoms if increased purulence of sputum is
one of the two symptoms
o For patients with severe exacerbation requiring mechanical ventilation
Inhaled Glucocorticoids in COPD
Help to reduce inflammation in the airways
May help to reduce exacerbations
Possibly slow the progression of respiratory symptoms
Have little effect on altering lung function
Not to be used alone in treating COPD
Combined with bronchodilators (LABA), in advanced COPD
o GOLD stages C and D
Phosphodiesterase-4 Inhibitor
Roflumilast
Mechanism of action: Roflumilast and its active N-oxide metabolite selectively inhibit
phosphodiesterase-4 (PDE4).

COPD-only medication, for risk category C and D

24-hour duration of action after single daily dose
Anti-inflammatory effects include suppression of cytokine release and inhibition of lung infiltration by
neutrophils and other leukocytes. Pulmonary remodeling and mucociliary malfunction are also
attenuated.
Side-Effect Profile
Diarrhea and weight loss are common in the first 6 months of therapy; merits close observation in
this time period
Headache
Anorexia, n/v
Dizziness
Back pain
Safety Information
Contraindicated in moderate to severe hepatic disease
Cytochrome p450: substrate of CYP1A2 (minor), CYP3A4 (major)
Pregnancy category C
Passes into breastmilk

Guidelines for Antibiotic Treatment

GOLD guidelines stratify by severity of exacerbation
o Group A: patients with mild exacerbation/no risk factors for poor outcome:
Beta-lactam, tetracycline, macrolide
o Group B: patients with moderate exacerbation with risk factor(s) for poor outcome:
Beta lactam-beta lactamase inhibitor (Augmentin)
o Group C and D: patients with severe exacerbations with risk factor(s) for P. aeruginosa infection:
Fluoroquinolone and PCN V.K
Delivery of Medication
MDI with CFCs vs. HFAeffective 12/07
Breath activated
Dry powder inhalers: diskus, capsule, etc.
Spacers: do you need one and which one?
Nebulizers: compressor vs. ultrasonic
Continuity of Care
Communication between PCP and hospital, PCP and family, PCP/family and school/camp
Consent?
Medication authorization for school and camp
Asthma action plans
Education! Asthma nurse? VNA for COPD
Improve quality of life and provide best possible care
Comanagement (asthma) during pregnancy may be needed

Diabetes Overview
Diabetes Mellitus Types
Type 1: an absolute deficiency of insulin secretion
Type 2: a combination of resistance to insulin action and inadequate compensatory insulin secretory
response
o Patients do not make enough insulin to keep blood glucose levels within target range
Diabetes Mellitus
Characterized by hyperglycemia
o Blood glucose levels in the high 100s, 200s, or 300s
Associated with major abnormalities in carbohydrate, fat, and protein metabolism
Poor glycemic control can lead to the development of long-term complications
o E.g., retinopathy, neuropathy, nephropathy, and cardiovascular disease
Diabetes Mellitus: Classification
Type 1: insulin dependent (~1020%)
o Most common in youth, can be diagnosed at any age
Type 2: insulin resistance (~8090%)
o Most common in adults, on the rise in youth
Sedentary lifestyle, diet, refined foods, and rising rates of obesity
Obesity could be associated with either type 1 or type 2 diabetes
Gestational (25% of all pregnancies)
o Ends after delivery but 4050% are at risk for type 2 diabetes
Secondary and other forms
o Maturity-onset diabetes of youth (MODY)
o Cystic fibrosisrelated diabetes (CFRD)

Differential Diagnosis: Type 1

Type 1: immune
Not overweight
Low endogenous insulin
Low C-peptide
o A proinsulin that is made at the same time as insulin
o Good indicator of insulin production
Positive autoantibodies
o Insulin antibodies
o Glutamic acid decarboxylase (GAD)
o Islet cell antibodies
Diabetic kitatosis (DKA): high ketone levels
o Produced when no insulin in production
o Body must break down fats instead of carbohydrates as a source of energy
o Ketones are the by-product of that process
Differential Diagnosis: Type 2
Type 2: nonimmune
Overweight (BMI: > 80 percentile)
High endogenous insulin levels
o Body must work hard to keep glucose levels within target range
High C-peptide
o Indicator of insulin production
Negative autoantibodies
Low ketone levels
Diabetes in Youth: Epidemiological Trends
Type 1:
o Increasing incidence/prevalence
o Shift towards younger age of onset
o More intensive in younger ages: more resistant and require higher doses
o Increasing frequency of DKA diagnosis
Type 2:
o Increasing occurrence due to obesity
o Programs started to encourage increasing physical activity and changing diet
o More likely to have a genetic component
ADA Diagnostic Criteria
Hemoglobin A1C >6.5% (Best indication for chronic hyperglycemia)
Fasting glucose >126 mg/dl (Hyperglycemia)
2-hour glucose >200 mg/dl
Random glucose >200 mg/dl
Symptoms: increase in thirst, hunger, urination, weight loss, and fatigue
Care for the Patient with Diabetes
Goal of diabetes management, to achieve nondiabetes numbers as close as possible to A1C Blood
glucose monitoring
Insulin/oral agents
Nutrition
Exercise
Education
Communication

Multidisciplinary team: endocrinologist, nurse, nurse practitioner, dietician, and mental health
support
Hemoglobin A1C
A glycoprotein formed when glucose binds to hemoglobin A in the blood
Typically measured 3 or 4 times a year
A1C goals are age-specific
o

A1C Recommendations for Nonpregnant People with Diabetes

Patient
Youth
Adults
Older Adults Healthy
Older Adults Complex/Intermediate
Older Adults Very Complex/Poor Health
Goals in Practice
To maintain normal growth and development
To avoid symptomatic hyperglycemia and hypoglycemia
To intervene early for high blood glucose and rising glycohemoglobins
To provide realistic expectations
To prevent parent/child burnout and isolation
To prevent deterioration of glycemic control during adolescence
To identify and treat behavioral/adjustment dilemmas
To provide positive medical experiences
Insulin
Main management method of type 1 diabetes
A hormone produced by -cells in the islets of Langerhans
Affects many organs
o Stimulates skeletal muscle fibers
o Stimulates liver cells
o Acts on fat cells
o Inhibits production of certain enzymes
o Triggers these effects by binding to the insulin receptor
Mechanisms of Insulin

Possible mechanism to decrease the blood sugar level

Increase insulin productions
Decrease secretion of glucagon
Decrease insulin resistance by increasing
sensitivity of inulin receptor sites
Decrease absorption of glucose from the GI Tract
Decrease resistance of glucose from the liver into
the blood stream by decreasing liver
glycogenolysis and liver gluconeogenesis
Decreasing eating by inhibiting the appetite center
and for stimulating the satiety center in the
Hypothalamus
History of Insulin
Discovered in 192122 by Frederick Banting and Charles Best at the University of Toronto
o Found by looking at -cells and the islets of Langerhans in dogs
o Manufactured by extracting from the pancreas of cows and pigs
First used to treat a 13-year-old boy with type 1 diabetes
Eli Lilly manufactured the first insulin using beef and pork
Before insulin, patients were managed with a very-low-carbohydrate diet
Patients may first be diagnosed after a significant weight loss
Insulin: Administration
Administered subcutaneously
Previously used conventional insulin therapy but moving towards intensive insulin therapy
o Conventional insulin therapy: one to two injections per day
o Intensive insulin therapy: mainstay of diabetes management
Diabetes Control and Complications Trial
More than three injections per day reduced the risk of retinopathy by almost 80%
o Neuropathy, nephropathy, and cardiovascular disease were also reduced
Intervention group: more than three injections per day
Control group: conventional therapy
Stopped the study at 3 years because intervention group did so well
In follow-up studies, intervention group continues to have fewer diabetes-related complications than
control group
Human Insulin Analogs
Work faster than previous insulin therapies
Target and regulate metabolism of carbohydrate, protein, and fats
Stimulate hepatic glycogen synthesis
Types of Insulin
Short acting
Rapid acting
o Rapid acting is most typically used
Intermediate acting

Long acting
o To maintain basal insulin
Administered subcutaneously via syringe, pen, or continuous subcutaneous infusion insulin pump
Some providers still mix insulin but less common
o When drawing insulin in a syringe, draw the clear insulin and then the cloudy.
Insulin Analogs
Insulin Lispro (Humalog) (1996)
Insulin Aspart (NovoLog) (2000)
Insulin Glargine (Lantus) (2002)
Insulin Detemir (Levemir) (2005)
Insulin Glulisine (Apidra) (2006)

Rapid-Acting Insulin
Matches the way insulin reacts in the body
Better match of food to insulin
Shorter duration of activity
Decreased frequency of hypoglycemia
Administered 15 minutes before meals
o Some situations may lead to insulin after a meal, e.g., a picky toddler
Can give half before meal and another half during the meal.
Clear insulin
Short-Acting Insulin
Regular insulin
Primarily used to treat diabetic ketoacidosis (DKA) as an IV insulin
Longer duration and onset
Usability not as flexible for patients and families
Administered 3060 minutes before meals
Less flexible than the rapid-acting insulin because it takes longer to be come effective

Insulin Types:
Rapid Acting and Short Acting
Insulin Type
Onset

Peak

Duration

Administration

Rapid Acting
Aspart (Novolog)

510 min

13 hr

35 hr

Glulisine (Apidra)

15 min

3090 min

35 hr

-Use within 510 min before or

just after a meal, or as needed for
hyperglycemia.
-Use within 15 min before or just
after a meal, or as needed for

hyperglycemia.
Lispro (Humalog)
Short Acting
Regular (Humulin,
Novolin)

15 min

14 hr

35 hr

-Use within 15 min before or just

after a meal, or as needed for
hyperglycemia.

3060 min

25 hr

612 hr

-Use 3060 min before a meal.

Intermediate-Acting Insulin
NPH insulin
Lasts 12 hours
o BID- good option for schoolers who have nobody to give them med during the day
Not commonly used now
Cloudy insulin
o When mixed, must be second insulin drawn up in syringe
Intermediate Acting Onset

NPH

12 hr

Peak

414 hr

Duration

Administration

1024 hr

It is important to determine when

you want the insulin to peak in
deciding when to take this dose.
May be taken at bedtime to
counteract dawn phenomenon.

Insulin Mixes
Referred to in terms such as 70/30 or 75/25
Rapid-acting insulin
Then part of it is buffered so it acts like an intermediate insulin
Typically administered as two daily doses, morning and evening, to cover all the meals and snacks
Not used as first treatment choice because it is not intensive
Insulin Types: Mixes
Onset

Peak

Duration

Administration

Use within 15 minutes before or

just after a meal.

Intermediate + rapid or short (pre-mixed)

Humalog Mix 75/25

15 min

17 hr

620 hr

Humalog Mix 50/50

15 min

15 hr

612 hr

Novolog Mix 70/30

1030 min

13 hr

Up to 24 hr

Humulin Mix 70/30

30 min

212 hr

24+ hr

Humulin Mix 50/50

3060 min

212 hr

1824 hr

Use 3060 minutes before a meal.

Usually given at least BID.

Long-Acting Insulin
Basal insulin
Typically injected once daily
Allows more flexibility for patients and families
Insulin Types: Long-Acting
Long-Acting

Onset

Peak

Duration

Detemir (Levemir) 1 hour

None

624 hr

Administration
Duration varies with dosage.
Use once or twice daily.

Glargine (Lantus) 1 hour

None

24 hr

Given once daily. Can be given

at any time of day, but should be
the same time every day.

Insulin Dosing
Initial Insulin Dosing
Based on pubertal stage of development and weight
Various regimens to adopt: BID dosing, TID dosing, and mixed regimens
Hypoglycemia
Primary side effect of insulin
Patients should expect at least one episode per week
Patients and families fear dead-in-bed syndrome
Frequent blood glucose monitoring and looking for patterns help prevent this and provide
reassurance
Non-DKA patient:
Prepubertal 0.250.5 units/kg/day
Pubertal 0.50.75 units/kg/day
Post-DKA patient:
Prepubertal 0.75 units/kg/day
Pubertal 1 unit/kg/day
Total daily dose should be divided as follows:
TID injection regimen:
o 2/3 of TDD is given before breakfast (2/3 as NPH and 1/3 as rapid-acting insulin; 1/3 of the
remaining TDD is given as predinner rapid-acting insulin (1/3) and prebedtime NPH(2/3)
BID injection regimen: Daily dosage: 0.5U/Kg
o 2/3 of TDD is given before breakfast and 1/3 of TDD is given before dinner
o 2/3 of each dose should be given as NPH and 1/3 as rapid-acting insulin
For example: Mr. Smith weights 247 pounds (112kg)
o He will take 56 U throughout the day (112 kg x 0.5U/kg = 56 U)
In the morning, he will take 37.2 U of 75/25 preparation
In the evening. He will take 18.7 U of 50/50 preparation
Insulin Side Effects
Primary symptoms of hypoglycemia:
Cardiovascular: pallor, palpitation, tachycardia
Central nervous system: fatigue, headache, hypothermia, loss of consciousness, mental confusion
Dermatologic: redness, urticaria
Endocrine and metabolic: hypoglycemia, hypokalemia
Gastrointestinal: hunger, nausea, numbness of mouth
Local: atrophy or hypertrophy of SubQ fat tissue; edema, itching, pain, or warmth at injection site;
stinging
Neuromuscular and skeletal: muscle weakness, paresthesia, tremor
Ocular: transient presbyopia or blurred vision
Miscellaneous: anaphylaxis, diaphoresis, local, and/or systemic hypersensitivity reactions

Drug Interactions
Increase hypoglycemic effect of insulin
Alcohol, anabolic steroids, beta blockers, chloroquine guanethidine, lithium carbonate, MAOI,
mebendazole, octreotide, pentamidine, phenylbutazone, pyridoxine, salicylates, sulfinpyrazone,
sulfonamides, tetracyclines
Decrease hypoglycemic effect

Asparaginase, acetazolamides, AIDS antivirals, calcitonin, corticosteroids, cyclophosphamides,

dextrothyroxine, diazoxide, diltiazem, dobutamides, epinephrine, estrogens, ethacrynic acid, isoniazid,
lithium carbonate, morphine sulfate, niacin, phenothiazines, phenytoin, nicotine, thiazide diuretics,
thyroid hormones

Insulin Regimens
Fixed doses
Sliding scales
BID injections
TID injections
Basal-bolus regimen
Modified basal-bolus regimen: uses long-acting, rapid-acting, and NPH insulin
Most intensive regimen is typically basal-bolus
Insulin Regimens
Regimens
Fixed doses
Sliding scales
BID injections
TID injections
Basal-bolus regime
Modified basal-bolus

Multiple Daily Injections / Basal- Bolus Therapy

Uses a long-acting (peakless or nearly peakless) insulin analog for basal insulin
Rapid-acting insulin analog to cover meals and correct elevated blood glucose readings
Basal-Bolus Therapy
Most common insulin regimen
May achieve optimal glycemic control
Allows for more flexibility
Mimics the way the body delivers insulin
Basal: long-acting insulin that keeps glucose within target range
Bolus: amount of insulin used to bring glucose down
Delivered via pen, syringe, or insulin pump
Basal and rapid-acting insulin used to cover the food and treat
hyperglycemia

Insulin Effect

Diluted Insulin
Used for patients who are very sensitive to insulin (even a 0.5 unit dose may be too much)
Often used for toddlers
Typically delivered in doses of 0.10 or 0.25 units
Referred to as U10: each line on the syringe is 0.10 of a unit
Humulin R U500
May be considered in people requiring more than 200 units a day
Allows 1/5 of the volume of insulin to be injected
Used in extreme insulin resistance
o Type 2 diabetes, diabetes patients being treated with long-term high-dose steroids
o Humulin R U-500 vial contains 20 ml
Insulin Algorithm
Algorithm for insulin therapy based on units of insulin administered per dose

Cochran E. et al. (2005). Dia Care, 28, 12401244.

Designing an Insulin Plan
Consider what works best for the patient:
o Can s/he do math?
o Can s/he count carbohydrates?
o Is s/he willing to count carbohydrates?
o Is s/he on a set schedule?
o Does s/he need flexibility?
o Is s/he needle-phobic?
o Is s/he willing to monitor blood glucose readings?
Consider the program.
Manage the insulin dose to bring glucose to target range.
Consider the cost.

Recognize that insulin choice is driven by insurance and can change frequently.

Target Blood Glucose Range

A number in the middle of the "target range"
Set by age
E.g adolescent target range: 90-130 mg/day
Target can be different for different times of day
Set target range higher for those more sensitive to insulin at night
Calculating the target
Target range 80120 mg/dl
Target 100 mg/dl
Insulin-to-Carbohydrate Ratio
Used to determine the amount of insulin used to cover carbohydrates to be consumed
Example: TDD is 85 units
o 450 rule: (450/TDD) = (450/85) = 5
o One unit of insulin will cover 5 grams of carbohydrates
Sensitivity/Correction Factor
The sensitivity factor or correction factor is the change in blood glucose brought about by 1 unit of
insulin
Sensitivity factor used to correct the bolus dose to bring an out-of-range blood glucose level into the
target range
Insulin Sensitivity Factor
1500 Rule: 1500/85 = 18
o 1 unit of Humalog/Novolog bg 18 mg/dl
1800 Rule: 1800/85 = 21
o 1 unit of Humalog/Novolog bg 21 mg/dl
1650 Rule: 1650/85 = 19
o 1 unit of Humalog bg 19 mg/dl
TDD is 85 units.
Basal-Bolus Calculation
Basal insulin consists of 3040% of total daily dose of insulin
85 .40 = 34
34 units of long-acting insulin at night

Calculating Bolus Worksheet

Target = ____ mg/dl
Insulin:carbohydrate ratio = 1 unit: ____ gr
Sensitivity factor = 1 unit: ____ mg/dl
Carbohydrates = ____ gr
Blood sugar = ____ mg/dl
Rapid-acting insulin dose = ____ units
Rules: Injected Insulin
Look for patterns for 35 days: e.g., continuously elevated at dinner
Consider what type of insulin the child is on, its peak, and its duration

Insulin doses adjusted in 10% increments

Rule out other causes of hyperglycemia: e.g., illness

Dose Adjustment Considerations

Factors affecting blood glucose
Illness
Medication steroids
Physical activity make patient more sensitive to insulin
Change in routine
Change in diet
Insulin omission to manage weight loss

Basal-Bolus Dosing Insulin Pump

Continuous Subcutaneous Insulin Infusion
The most precise way to mimic normal insulin secretions
Provides continuous insulin administration to normalize blood glucose levels throughout a 24-hour
period
Basal insulin consists of 3040% of total daily dose of insulin.
Previously basal and bolus were split 50-50 (until controlled study in Japan).
If basal dose is rising and being used more to cover meals, patient should be using the bolus dose.
If basal dose is too high and eating patterns change, there may be more episodes of hypoglycemia.
If patient needs to eat to cover a low, basal dose may need adjustment.
Basal dose: TDD multiplied by 0.4 (40% of total dosage)
Insulin Delivery Under Pump Therapy (CSII)
CSII Regimen
12 am .250 units/hour
6 am .375 units/hour
11 am .350 units/hour
4:30 pm .400 units/hour
8 pm .450 units/hour

http://www.disetronic.com
Criteria for Successful Pump Management
Child must want pump; not only parents or health care team
Good family and school support
Demonstrated comfort level with conventional management tools
Diabetes team with 24-hour support system
Ability to count carbohydrates
Insulin Pumps
o Animas Ping
o Medtronic MiniMed
o OmniPod
o AccuChek Spirit Combo

t: slim
Pump Benefits
Improvement in blood glucose levels is possible with pump
Greater flexibility, including flexibility of timing and size of
Meals and snacks (less/more)
Exercise (timing, duration and intensity)
Ability to intensify blood sugar control
Fewer severe low blood sugars
Immediate access to insulin
Ease at delivering insulin
More predictable insulin absorption from a continuous insulin depot
Dawn Phenomenon effects are easier to manage with the basal rate and can be set to accommodate
the rise in insulin requirements overnight
Basal insulin rates can be quickly changed to accommodate growth spurts in children or increased
insulin needs during pregnancy
Improvement in the safety profile is possible
Reducing the basal rate during periods of low physiological requirements can minimize
nocturnal or daytime hypoglycemia
Using a temp basal rate to meet short-term physiological needs
o

Pump Challenges
Increased frequency of monitoring
Increased chance of hyperglycemia and DKA due to crimped infusion sets, air bubbles, and
dislodged cannula
Only uses rapid-acting insulin, not long-acting insulin
Therefore, if mechanical failure, air in the tubing, or other issues occur, ketones can start to
develop within hours
Potential for skin abscess
Change in hypoglycemic symptoms
Constant attachment to pump
Technical or mechanical failure is possible with a pump
Weight gain is possible with improved glycemic control
Cost of insulin pumps usually almost $6,000 not including cost for supplies
Tools to Pump Success
Professional diabetes support team including school nurse in place
Regular medical follow-up
Parents' ability and willingness to manage the pump
Troubleshooting Hyperglycemia Insulin Pump Therapy
Red, tender, and swollen catheter site: the insulin not being absorbed correctly and adds to high
blood glucose
Seen only in rapid acting insulin
Leakage, breakage, or kinking of tubing
Battery failure
Empty reservoir or cartridge
Mechanical failure
Improper basal rate programming
Air in tubing

Illness
Menstrual cycle fluctuations
Insulin resistant before menses
Omitted bolus or improper dosing
Crimping of cannula

Insulin Pens and Needles and Insulin Considerations

Insulin Pen Consideration
It is more portable than traditional syringe and vial.
Injection technique is the same as syringe except that once pen needle has been injected into the skin,
needle needs to be held in place for 5 to 10 seconds.
Insulin Injection Tips
Select site that has no hypertrophy or scar tissue.
Occurs when site is overused
Use insulin that is at room temperature.
Make sure that air bubbles are purged from delivery device.
Rotate injection sites.
Insulin Injection Sites

Factors Effecting Insulin Absorption

Heat: increases absorption rate
Site: absorbs faster from abdomen
Lipohypertrophy: delays insulin absorption
Insulin dose: large doses have a delay in action and duration
Insulin Storage and Expiration Date
Unopened insulin should be refrigerated; it can be kept until its expiration date.
Insulin being used need not be refrigerated; it should be stored at room temperature between 36 F (2
C) and 86 F (30 C).
Insulin is dated by the manufacturer and should be used before the expiration date.
Opened insulin in use should be stored at room temperature or in a refrigerator and discarded after 28
days.
In-use prefilled pens/cartridges of aspart, glulisine, lispro, detemir, glargine, and regular should be stored
at room temperature and are good for 28 days.
Premixed insulin and intermediate-acting insulin (NPH) cartridges and pens can be stored at room
temperature for a maximum of 10 to 14 days (must be rolled prior to use).
Risk Factors for Complications
Uncontrolled diabetes: HbA1C >8%
Infrequent follow-up diabetes care
Identify barriers to improving diabetes control
Goal: Implement intensive therapy teamwork: family, school, community, health care.
Treatment for Severe Hypoglycemia
Glucagon (Gluca-Gen: Glucagon emergency kit)
o Management of hypoglycemia, promotes hepatic glycogenolysis and glucogenesis, causing
an increase in blood glucose levels

o
o
o

Dose: infants/children 20 kg .020.03 mg/kg; children 20 kg and adults 1 mg

Administration: IM or SQ
Side effects: nausea, vomiting, hypertension, tachycardia

Minidose Glucagon
Used when a child or adolescent with type 1 diabetes is unable to consume or absorb oral
carbohydrate because of nausea and vomiting associated with gastroenteritis
Used to prevent impending hypoglycemia
Drawn up in a standard U-100 insulin syringe
Two "units" on the insulin syringe for children ages 2 years and one unit per each year of age in children
ages 215 years (150 mg)
Patients ages >15 years receive only 15 units
Monitor blood glucose q 30 minutes for the first hour, then hourly until blood glucose is at 100 mg/dl
If blood glucose unchanged after 30 minutes, may repeat and double the dose
Summary
Significantly more patients today practice intensive diabetes Rx as evidenced by
o More patients receiving 3 injections/day
o More patients performing BG monitoring 4/day
o More patients using CSII
Intensification of therapy leads to
o Improved glycemic control (lower A1C)
o No significant increase in z-BMI
o 50% fewer hypoglycemic events, 25% fewer ER visits
Future: CGM and closing the loop to improve and normalize glycemic control

Oral Agents and Type 2 DM

Diabetes Treatment: Overview
Algorithm for oral diabetes medication
Monotherapy, combination oral therapy, combination therapy vis-a-vis oral medication, insulin, and
GLP1
Criteria for Diagnosing Diabetes
Symptoms
Increased thirst, hunger, and urination
Plasma glucose 200 mg/dL

Fasting glucose level

126 mg/dL
Two-hour oral glucose tolerance
200 mg/dL
Criteria for Diagnosing Diabetes (cont.)
Hemoglobin A1C
6.5%
Convenient but not as accurate
Can't diagnose gestational diabetes
Not for patients with conditions that affect turnover rate of red blood cells (iron deficiencies)
Helpful for finding prediabetes (between 5.7 and 6.4%)
The Complexity of Diabetes
More than just glucose issue
Chronic disorder characterized by abnormalities in glucose, fat, and protein metabolism
Over time, most patients will develop microvascular, macrovascular, and neurologic complications
Diabetes and Depression
Three times more common in diabetes patients
o Type 1 and type 2
o More common in women
o Not clear if complications cause depression or vice versa
Sometimes patients lack clear goals; feel discouraged, overwhelmed
Patients sent home to take care of themselves, causing anxiety
Constant concern about food and eating
Uncomfortable interactions with family ("diabetes police")
Final Thought
The most powerful advance against diabetes isn't a drugit's a partnership.

Diabetic Control
DCCT (type 1 diabetes)
Tight control decreased microvascular and neurological complications, increased risk of hypglycemia
EDIC: control early in diabetes has positive long-term effects
UKPDS (type 2 diabetes)
Tight control decreased microvascular complications, but no change in macrovascular complications
Lowering BP decreased microvascular and further decreased macrovascular complications
ACCORD
Tight control for those with CAD risk; may not be beneficial

Glycemic Control Goals

Fasting/preprandial (mg/dL)

Normal

Goal

100

70130

23 hr postprandial
Bedtime glucose

90150

Glycohemoglobin (A1C)(%)
Type 1 Diabetes
o 10% of diabetes patients have type 1.
Autoimmune destruction of beta cells
+GAD (glutamic acid decarboxylase) antibodies
Ketone production
Injected insulin necessary
Multiple injections give better control
Onset often sudden
Increased thirst (polydipsea), increased hunger (polyphagia), increased urination (polyurea),
weight loss
LADA (latent autoimmune diabetes in adults) can mimic type 2 diabetes
Type 2 Diabetes
90% of diabetes patients have type 2.
Resistance to endogenous and exogenous insulin
75% of patients are obese at diagnosis
Impaired first- and second-phase insulin secretion. Insulin levels can start high and then drop off to
normal and low levels.
Increased hepatic glucose production
Ketosis is unlikely
Onset often insidious with no or mild "polys." 50% of patients are diagnosed at their first cardiac event,
and diagnoses are increasing in children.
Natural History of Type 2 Diabetes
Insulin Resistance
o Normally, insulin binds to specific receptors on cell surface, which activates glucose transport.
Insulin resistance = post binding defects
Occurs in hepatic and muscle tissue
Decreased glucose transport
Decreased glycogen synthesis
Choosing the Right Treatment
Diabetes Assessment
Complete history with emphasis on:
Confirmation of diagnosis
Review of treatments, outcomes, education
Factors that affect glucose control
Current lifestyle/psychosocial issues
Medications

Complications of diabetes
Complete exam: emphasis on complications
Labs and Goals
Lab assessment
o Glucose, glycohemoglobin
o Lipids
o Renal and liver functions
Establish goals
o SBGM/glycohemoglobin
o Weight, meal plan, activity plan
Pharmacologic treatment
Algorithm for Treatment

Choosing the Right Treatment

Treat the person and the physiologic defect.
Is the person obese or less obese?
o Obese people are usually insulin resistant.
o Less obese people may be more insulin deficient.
o Are there other signs of insulin resistance, e.g., hypertension, hyperlipidemia?
Is the patient's diabetes new or long term?
o New cases indicate lack of first-phase insulin secretion.
Lack of first phase = high postmeal
o Long-term cases see decreased first- and second-phase insulin.
High BG all day
Decide between monotherapy or combination therapy.
Treatment for Obese Patients
Biguinides: decrease hepatic glucose production, lower fasting glucose
GLP-1 receptor agonists: stimulate insulin production, slow gastric emptying, decrease hepatic glucose
production, decrease appetite
Thiazolidinediones: improve glucose transport
Treatment for Less Obese Patients
Insulin secretagogues: Stimulate beta cell insulin production

Treatment for Mild Glucose/Postprandial Elevations

Alpha-glucosidase inhibitors: slow carb breakdown/absorption
Meglitinide or d-phenylalanines: increase insulin secretion
DPP-4 inhibitors: inhibit breakdown of incretins
GLP-1 receptor agonists
Bile acid sequestrant: action unclear
Centrally acting agents: affect neurotransmitters

Insulin Sensitizers
o Biguanides
o Metformin (Glucophage)
o Metformin extended release
o Thiazolidinediones
o Rosiglitazone (Avandia)
o Pioglitazone (Actos)
Biguanides
Used as first-line therapy unless contraindicated, and in the obese (insulin resistant) with normal
liver and renal functions.
Decrease hepatic glucose production
Inhibit gluconeogenesis
Stimulate glucose uptake in skeletal muscle and adipocytes
Cell receptors
Glucose transport GLUT 4
Associated with 1- to 2-kg weight loss
Usually do not cause hypoglycemia

Risk of Lactic Acidosis

To prevent lactate buildup do not use in patients with renal dysfunction.
Males: creatinine 1.5 mg/dL
Females: creatinine 1.4 mg/dL
Abnormal creatinine clearance: 80 years old
Also avoid use in people with liver dysfunction, alcohol abuse/binge drinking, CV collapse (acute
MI or acute CHF), and anyone undergoing major surgical procedure.
Stop metformin day of contrast study, then recheck creatinine in 48 hours. If levels are okay, metformin
can be restarted.
Metformins
o Initially, take with food to minimize gas and diarrhea.
Glucophage
Starting dose: 500 mg qd/bid; 850 mg qd
Maximum dose: 2,550 mg/day
Take with meals bidqid
Riomet (oral solution)
5 mL = 500 mg
Glucophage XR (extended release)

Starting dose: 500 mg qd; 750 mg qd

Maximum dose: 2,000 mg/day or 1,000 mg bid
Take with evening meal
Fortamet and Glumetza (extended release)
Starting dose: 500 mg1,000 mg qd
Fortamet maximum dose: 2,500 mg/day
Glumetza maximum dose: 2,000 mg/day
Take with evening meal

Thiazolidinediones (TZDs)
TZDs increase risk for new or worsening macular edema and may increase risk of bone fracture.
TZDs decrease hepatic glucose production, do not cause hypoglycemia, and are associated with weight
gain. Pioglitazone may improve lipid profile.
Rosiglitazone (Avandia)
No significant drug interactions
Starting dose: 4 mg qd or 2 mg bid
Adjust dose after 812 weeks
Maximum dose: 8 mg qd in single or divided doses
Pioglitazone (Actos)
Drug interactions: OCs not studied; may interact with ketoconazole
Starting dose: 1530 mg qd
Adjust at 4- to 6-week intervals
Maximum dose: 45 mg
Thiazolidinediones: Who and How
Typically used in obese patients without liver disease or severe heart disease.
LFTs should be at baseline, then check periodically.
TZDs can cause or worsen CHF. Risk increases with addition of insulin. Do not use rosiglitazone
with insulin.
Contraindicated in Class III or IV heart failure.
TZDs improve glucose transport into cells by binding to peroxisome proliferator-activated receptors
(PPARs), and affect multiple genes. Protein production affects insulin sensitivity, perhaps inflammation
(increases apidonectin).
Rosiglitazone Update
1. Usage may be associated with increased risk of MI, but not CV, mortality.
2. Compared to pioglitazone, rosiglitazone use may be associated with increased risk of stroke, CHF, and
all cause mortality. Both TZDs increase risk of CHF.
3. Most of these data are derived from meta-analyses and uncontrolled studies. In November 2013 the FDA
announced it is considering removing restrictions.
Risk Evaluation and Mitigation Strategy for Rosiglitazone
HCPs must now enroll in the REMS program to prescribe rosiglitazone, pharmacists must enroll to
dispense it, and patients must be enrolled by their physicians to begin or continue receiving it.
HCPs have to attest to and document the patient's eligibility if they believe the patient is a candidate for
rosiglitazone.
Patients must review statements describing CV safety concerns and sign acknowledgement of
their understanding.
Current users can only continue usage if they acknowledge and document they understand the
risks.
Patients not already taking rosiglitazone can receive it only if they're unable to achieve glycemic control
on other meds, and, in consultation with their HCP, decide not to take pioglitazone for medical reasons.
Pioglitazone Update

May be associated with increased risk for bladder cancer, but most data are derived from meta-analyses
and uncontrolled studies.
Do not use in people with active bladder cancer, and use caution in people with a history of bladder
cancer.
Metformin vs. TZD
Metformin can affect GI.
Metformin is less expensive.
Metformin is associated with weight loss; TZDs are associated with weight gain.
Metformin can't be used with renal disease; TZDs can.
Metformin doesn't cause edema; TZDs can.

Insulin Secretagogues
Classes of Secretagogues
Meglitinides: repaglinide (Prandin)
Amino acid derivatives: nateglinide (Starlix)
Sulfonylureas: long and short acting
Insulin Secretagogues: Who and How
Intended for the "less obese" patient with type 2 diabetes of longer duration, and decreased insulin
production
How they work:
Stimulate release of insulin from beta cells
Bind to cell receptor, inhibit potassium efflux, depolarize beta cell
Decrease hepatic glucose production
Potential for hypoglycemia
Avoid/use with caution in patients with liver and renal disease to prevent prolonged hypoglycemia.
Long-Acting Sulfonylureas
Generic/Trade
Glyburide/Micronase or Diabeta
Micronized Glyburide/Glynase
Glimepiride/Amaryl
Glipizide Extended Release/Glucotrol XL
Short-Acting Sulfonylureas
Glipizide/Glucotrol
Usually bid
2.540 mg qd (5, 10 mg)
30 minutes before meal
For lowering glucose, a small amount
Less potential for prolonged hypoglycemia
Meglitinides: Repaglinide (Prandin)
Chemically unrelated to sulfonylureas, making it an important tool for patients with sulfa allergies.
They stimulate the release of insulin from beta cells. The binding that occurs differs from sulfonylureas,
and the action is shorter. There is risk for hypoglycemia.
Can be taken 030 minutes before mealtime, 24 times/day. If a meal is skipped or added, dose should
be skipped or added as well.

Dose range: 0.54 mg; maximum dose 16 mg/day.

Not for use with NPH insulin due to increased risk for myocardial ischemia.
Contraindicated with gemfibrozil; risk of protracted hypoglycemia.

Amino Acid Derivatives: Nateglinide (Starlix)

Much like meglitinides, binding and chemical composition is unrelated to sulfonylureas; they stimulate
the release of insulin from beta cells, and the action is shorter. Risk remains for hypoglycemia.
Can be taken 030 minutes before mealtime, tid. If a meal is skipped or added, dose should be skipped
or added as well.
Dose: 60120 mg; maximum dose 360 mg/day
Repaglinide or Nateglinide vs. Sulfonylureas
Short-acting secretagogues diminish risk of protracted hypoglycemia
More mealtime flexibility with short-acting secretagogues
Potency
o Sulfonylureas more potent
o Repaglinide/Nateglinide won't lower A1C as much
Sulfa allergies
o Avoid sulfonylureas altogether
Cost (example of cost difference by some pharmacy programs)
o Max dose of Prandia per month = $199
o Max dose of second generation sulfonylureas per month = $11$62
Alpha-Glucosidase Inhibitors (AGIs)
For postmeal glucose elevations (newer diabetes)
Arcabose (Precose)
Miglitol (Glyset)
AGIs: Who and How
Typically used for overall milder glucose elevations, they work by delaying absorption of carbohydrates
by inhibiting alpha-glucosidase in brush borders of intestines. Check glucose one hour after meal.
They don't cause hypoglycemia, but hypoglycemia from combination therapy should be treated with
glucose (dextrose), not sucrose.
Side effects include flatulence, soft stool, and diarrhea.
Contraindicated in chronic intestinal diseases. Arcabose contraindicated in liver disease. Avoid in renal
dysfunction.
AGIs: Dosing
Arcabose (Precose)
Starting dose: 25 mg qd taken early in meal for Weeks 12
Increase to 25 mg bid in weeks 34
Increase to 25 mg tid in weeks 512
Can increase to 50100 mg tid
Miglitol (Glyset)
Starting dose: 25 mg qd-tid taken early in meal for Weeks 13
Increase dose after 48 weeks
Maximum dose 100 mg tid
DPP-4 Inhibitors
Dipeptidyl peptidase-4 inhibitors are used for postmeal glucose elevations.
They are weight neutral and do not result in hypoglycemia when used as monotherapy.

There is concern that DPP-4 inhibitors increase risk of pancreatitis.

Sitagliptin (Januvia)
Saxagliptin (Onglyza)
Linagliptin (Tradjenta)
Alogliptin (Nesina)
Incretins
Incretin hormones include:
Glucagon-like peptide-1 (GLP-1)
Glucose-dependent insulinotropic polypeptide (GIP)
Incretin hormones are released from the small intestine in response to food, resulting in:
Glucose-dependent insulin release from cells
Decreased glucagon release
Incretin hormones are broken down by DPP-4. DPP-4 inhibitors slow the inactivation of incretins.

Sitagliptin (Januvia) Dosing

Used as monotherapy or in combination with metformin or TZD. Available in
25-, 50-, and 100-mg tabs.
Normal renal function
100 mg once daily, unrelated to meals
CrCl >30 mL/min but < 50 mL/min
(creat 1.7 to 3.0 in men or >1.5 but 2.5 in women)
50 mg once daily
CrCl (creat >3.0 in men or creat >2.5 in women, or if on dialysis)
25 mg once daily
Saxagliptin (Onglyza) Dosing
Used as monotherapy or in combination with metformin, TZD, or sulfonylureas. Decrease dose if using
strong CYP3A4/5 inhibitors, such as ketoconazole. Available in 2.5- and 5-mg tabs.
CrCl >50 mL/min
5 mg once daily
CrCl
Do not exceed 2.5 mg daily
Not studied in end-stage renal disease.
Linagliptin (Tradjenta) Dosing
1. Used as monotherapy or in combination with metformin, TZD, or sulfonylureas.
2. No need to adjust dose for renal disease. Dose 5 mg once daily.
3. Avoid if using strong CYP3A4 inducer, such as rifampin, as it will reduce linagliptin's efficacy.
Alogliptin (Nesina) Dosing
Used as monotherapy in combination with metformin, TZD, sulfonylureas, or insulin.
Decrease dosage in renal impairment:
CrCl 60 mL/min
25 mg once daily
CrCl >30 mL/min but
12.5 mg once daily
CrCl
6.25 mg once daily
Postmarketing reports demonstrate hepatic failure, sometimes fatal.

SGLT2 Inhibitors
SGLT2 inhibitor is short for sodium-glucose cotransporter 2 inhibitor. There are two types:
Canagliflozin (Invokana)
Dapagliflozin (Farxiga)Action of SGLT2 Inhibitors

SGLT2 inhibitors block reabsorption of glucose by the kidney and increase excretion of glucose in urine
by inhibiting SGLT2. The mechanism of action results in a positive test for urine glucose.
Side effects include hypotension (especially in older patients), dehydration, hyperkalemia, decreased
renal function, genital mycotic infections, UTI, increased LDL cholesterol, and weight loss.

Canagliflozin (Invokana)
Used as monotherapy or with metformin, sulfonylureas, pioglitazone, and insulin.
Dosing
If GFR < 45 mL/min: do not initiate use and discontinue use if already on drug.
If GFR > 45mL/min: start with 100 mg daily with first meal of day.
If GFR between 45 and 60 mL/min: limit to 100 mg daily.
If GFR 60mL/min: increase to 300 mg daily.
Interactions
UGT enzyme inducers (rifampin, phenytoin, ritonavir, phenobarb) may decrease canagliflozin
efficacy.
Canagliflozin increases digoxin concentration.
Dapagliflozin (Farxiga)
Used as monotherapy or with metformin, sulfonylureas, sitagliptin, pioglitazone, and insulin. Do not use
in bladder cancer, and use caution if the patient has a history of bladder cancer.
Dosing
If GFR < 60 mL/min: do not initiate use and discontinue use if already on drug.
If GFR 60 mL/min: start with 5 mg daily in morning, increasing to 10 mg daily if needed.

New Use for Other Medications

Colesevelam (Welchol)
Typically used to lower LDL cholesterol, either as monotherapy or with a statin.
In type 2 diabetes, colesevelam is used as adjunct therapy, not primary therapy. Its glucose-lowering
mechanism is unclear. Colesevelam can further increase triglycerides when used with insulin or
sulfonylureas.
Dosing
Tablets: six 625-mg tabs once daily or three tabs twice daily
Oral suspensions: one 3.75-g packet once daily or one 1.875-g packet twice daily, in water, with
meals
Contraindications
History or risk of bowel obstruction
Triglycerides >500 mg/dL
History of hypertriglyceridemia-induced pancreatitis
Colesevelam reduces the absorption of some medications, so they should be dosed 4 hours before
colesevelam. Such medications include thyroid treatments, dilantin, oral contraceptives, and warfarin.
Cycloset (Bromocriptine Mesylate)
Cycloset's glucose-lowering effect is unclear, but it is thought that daily morning administration
normalizes hypothalamic neurotransmitter activities that affect the glucose-intolerant state. It improves
postprandial glycemic control without increasing plasma insulin concentrations.
Side effects

Low blood pressure, dizziness, fainting, nausea, headache

Use with caution when taking antihypertensives
May exacerbate psychotic disorders
May alter the effectiveness and safety of highly protein-bound therapies
Cycloset is contraindicated if the patient is taking ergots or has syncopal migraines. It is predominantly
metabolized in the liver, so caution should be used if liver disease is present.
Dosing
0.84.8 mg once daily
Taken with food within 2 hours of waking
Combination Therapy
The When, Why, and How of Combination Therapy
Combination therapy can be started at the onset of treatment or when monotherapy has been deemed less
than optimal.
Targets different defects
May lower glucose further
May decrease side effects with lower doses
May postpone initiation of insulin
When beginning combination therapy, continue the current OA, then add a low dose of a second OA and
adjust the dose accordingly.
More Examples of Combination Therapy

Examples of Combination Therapy

Sulfonylurea + metformin
Sulfonylurea + acarbose (Precose)
Sulfonylurea + miglitol (Glyset)
Sulfonylurea + TZD
Sulfonylurea + GLP-1 agonist
Sulfonylurea + colesevelam
Repaglinide (Prandin) + metformin
Repaglinide (Prandin) + pioglitazone
Metformin + acarbose (Precose)
Metformin + TZD, Metformin + colesevelam

Effect of Sitagliptin and Metformin on Glucose Control

Fixed Combination Therapy

Glucovance (metformin and glyburide)
Metaglip (metformin and glipizide)
ACTOplus met (metformin and pioglitazone)
PrandiMet (repaglinide and metformin)
Duetact (glimepiride and pioglitazone)

Sitagliptin (Januvia) + metformin

Sitagliptin (Januvia) + thiazolidinedione
Sitagliptin (Januvia) + sulfonylurea
Saxagliptin (Onglyza) + thiazolidinedione
Saxagliptin (Onglyza) + metformin
Saxagliptin (Onglyza) + sulfonylurea
Linagliptin (Tradjenta) + thiazolidinedione
Linagliptin (Tradjenta) + metformin
Linagliptin (Tradjenta) + sulfonylurea
Alogliptin (Nesina) + Metformin
Alogliptin (Nesina) + pioglitazone

Janumet (sitagliptin and metformin)

Kazano (alogliptin and metformin)
Kombiglyze (saxagliptin and metformin ER)
Juvisync (sitagliptin and simvastatin)
Glucovance (Glyburide and Metformin)
Same precautions for sulfonylureas only. Same liver and kidney issues as for metformin only.
Dosing
o Take with food qd or bid
o 1.25 mg/250 mg
o 2.5 mg/500 mg
o 5 mg/500 mg
Non-Insulin Injectables
The glucagon-like peptide 1 (GLP-1) receptor agonist is a non-insulin injectable.
An agonist is a drug that combines with a receptor on a cell to produce a physiological reaction.
Non-insulin injectables include:
o Exenatide (Byetta)
o Liraglutide (Victoza)
o Exenatide extended-release (Bydureon)

GLP-1 Modulates Numerous Functions

Effects of GLP-1
Upon food ingestion, GLP-1 is secreted into the circulation from L cells of the small intestine.
GLP-1 increases beta-cell response by enhancing glucose-dependent insulin secretion.
GLP-1 decreases beta-cell workloadhence the demand for insulin secretionby
Regulating the rate of gastric emptying such that meal nutrients are delivered to the small
intestine and, in turn, absorbed into the circulation more smoothly, reducing peak nutrient
absorption and insulin demand (beta-cell workload)

Decreasing postprandial glucagon secretion from pancreatic alpha cells, which helps to maintain
the counterregulatory balance between insulin and glucagon
Affecting the central nervous system, resulting in increased satiety (sensation of satisfaction with
food intake) and a reduction of food intake
Reducing postprandial glucagon secretion
GLP-1 has an indirect benefit on beta-cell workload since decreased glucagon secretion will produce
decreased postprandial hepatic glucose output. By decreasing beta-cell workload and improving betacell response, GLP-1 is an important regulator of glucose homeostasis.
Exenatide (Byetta)
Incretin mimetic
Incretin: glucagon-like peptide-1 (GLP-1)
Action
Enhances glucose dependent insulin secretion
Decreases gastric motility
Decreases hepatic glucose production
Increases satiety and causes modest ongoing weight loss
Insulin glargine can be used with exenatide.
Side effects include nausea. There have been recent reports of pancreatitis and renal failure.
Dosing
5 mcg bid subcutaneously at or within 60 minutes before meals for one month
After one month, increase to 10 mcg bid (prefilled pen)
Cut sulfonylurea dose in half to prevent hypoglycemia
Exenatide Extended-Release (Bydureon)
Bydureon caused thyroid C-cell tumors in rodents. Thus, the drug is contraindicated with personal or
family history of medullary thyroid carcinoma or MEN 2.
Side effects include nausea. A risk of pancreatitis is unclear.
Dosing
o 2 mg subcutaneously, once weekly
o Decrease sulfonylurea dose to prevent hypoglycemia

Liraglutide (Victoza)
Incretin mimetic
Incretin: glucagon-like peptide-1 (GLP-1)
Action
Enhances glucose-dependent insulin secretion
Decreases gastric motility
Decreases hepatic glucose production
Increases satiety and leads to modest ongoing weight loss
Use as type 2 diabetes as adjunct therapy if not optimally controlled on a thiazolidinedione, metformin, a
sulfonylurea, or metformin and a sulfonylurea.
Liraglutide has caused thyroid C-cell tumors in rodents, and thus is contraindicated in setting of personal
or family history of medullary thyroid carcinoma or MEN 2.
Side effects include nausea. A risk of pancreatitis is unclear.
Dosing
0.6 mg subcutaneously, once daily, for one week
After one week, increase to 1.2 mg daily
Further increase to 1.8 mg subcutaneously
Decrease sulfonylurea dose to prevent hypoglycemia

Liraglutide vs. Glimepiride as Monotherapy

Garber et al., Lancet, 2009; 373:473-481.

Exenatide vs. Liraglutide: Weight Loss

Buse et al., Diabetes Care, 2010; 33:1300-1303.

The Implications of Failure
Not all up to patient
Progression of diabetes
UKPDS
Oral Therapy and Insulin
If:
FPG > 130, or
2-hour postprandial > 180, or
A1C > 7%
Then:
Add third OA, or
Add exenatide, or
Add insulin
Glucose Level
Correction of the fasting glucose level by OM insulin may improve OA action.
Intermediate-acting insulin at bedtime, or
Basal insulin, e.g., glargine (Lantus) or detemir (Levemir) at bedtime, or
70/30, 50/50, 75/25 aspart insulin at supper
Oral Therapy and Insulin Combinations
Sulfonylurea + insulin
Metformin (Glucophage) + insulin
Acarbose (Precose) + insulin
Pioglitazone (Actos) + insulin
Repeat, Review, Reinforce
Consider
o Type of diabetes
o Obesity level
o Physiological defects that influence hyperglycemia
o Actions of medications

Choose most appropriate medication

o More than one correct treatment
o Most patients need combination therapy
Review case with trusted coworker
o Plan, assess, and evaluate
Changing Strategies: Diabetes
Former Paradigm
Diet and exercise
Reduce FPG levels
Insulin necessary for
glucose control