Saint Anselm College Continuing Nursing Education Manchester, NH Diabetic Pharmacology Faculty: Deb Boles, MS, RPh Clinical Pharmacy Manager, Lowell General Hospital Lowell, MA Contact hours: 2

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Saint Anselm CollegeContinuing Nursing
EducationManchester, NHDiabetic
PharmacologyFaculty Deb Boles, MS, RPhClinical
Pharmacy Manager, Lowell General HospitalLowell,
MAContact hours 2

• This online program is available until December
  31, 2016
• In order to receive contact hours, you must
• Listen to entire program
• Complete the post-test and the evaluation
• Once you have submitted your evaluation, you will
  then be sent your certificate of completion.
• Thank you!

2
Disclosure

• The presenter has no financial or other interest
  in any commercial company which could influence
  the content of this presentation. There is no
  commercial support for this program. The planning
  committee has nothing to disclose.

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DIABETES

• Deb Boles, MS,RPh
• Clinical Pharmacy Specialist

4
Objectives

• Distinguish the three types of known diabetes
• Discuss the different types of insulin including
  new therapies
• List potential therapies for type 2 diabetes

5
Diabetes impact

• Effects 15 million americans (8 of the
  population)
• 3rd leading cause of death behind cancer
• Estimated 12 million people have it and dont
  know it

6
Incidence of Diabetes in the US
Centers For Disease Control and Prevention.
Diabetes Data and Trends. .http//apps.nccd.cdc.g
ov/DDT_STRS2/NationalDiabetesPrevalenceEstimates.a
spx?modeDBT
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Glucose and Insulin Production
8
Normal insulin function

• Blood glucose increases after meal
• Pancreas secretes insulin to help glucose enter
  cells
• Negative feedback loop
• Fasting state slow release of insulin

9
3 Major Classifications of Diabetes
Cause Incidence
Type 1 Auto-immune mediated destruction of insulin-producing beta cells in the pancreas Less than 10 of patients with diabetes
Type 2 Peripheral insulin resistance and a relative deficiency of insulin More than 90 of patients with diabetes
Gestational Insulin resistance caused by pregnancy increases risk for type 2 diabetes later in life 3-5 of pregnancies
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Type 1 (IDDM)

• Only accounts for 5-10 of all cases
• Strong genetic component
• Environmental trigger
• Insulin dependent

11
Type 1 Pathogenesis

• Beta-cells in pancreas are destroyed leading to
  total insulin deficiency
• Abnormal activation of T-cells mediated immune
  system
• In general destruction is more rapid when occurs
  at younger age

12
Management of Type 1

• Appropriate insulin delivery
• Self monitor of blood glucose concentrations
• Nutritional planning
• Avoidance of hypo or hyperglycemia
• Screening for treatment of diabetes-related
  complications

13
History of insulin

• For decades only animal source
• 1980s recombinant technology
• Utilizes E. Coli
• Insulin producing genes

14
Insulin Properties
Type of Insulin Onset Peak Duration
Rapid Acting Aspart (Novolog) Lispro (Humalog) Glulisine (Apidra) 15-30 minutes 90 minutes 3-5 3-5 3-5
Short Acting Regular 30-60 minutes 2-3 hours 6-10
Intermediate Acting NPH 2-3 hours 4-10 hours 12-18 hours
Long-Acting Detemir (Levemir) Glargine (Lantus) 2-3 hours 2-3 hours No pronounced peak No pronounced peak 24 hours 24 hours
Roach P. New Insulin Analogues and Routes of
Delivery Pharmacodynamic and Clinical
Considerations. 200847(9)595-610.
15
Rapid acting

• Three agents
• Lispro(Humalog)
• Aspart (Novolog)
• Glulisine (Apridra)
• Higher levels earlier
• Short duration of action
• Helps reduce post-prandial hyperglycemia
• Increase patient compliance

16
Insulin glulisine (Apridra)

• Two amino acid changes
• Bind to Insulin receptors affecting glucose
  transfer across cells
• 12 week study premeal versus postmeal

17
Insulin aspart (Novolog)

• Single amino acid change
• Glucose lowering effects better than regular
• Better post-prandial control
• Comparable to lispro

18
Rapid acting mixes

• Rapid acting cant be mixed with NPH
• Mixes are plain with protamine bound product
• Lispro 25/75 or 50/50
• Aspart 30/70 or 50/50

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Rapid Acting vs. Regular insulinBenefits of
Regular Insulin

• Rapid-Acting

• Regular

• Expensive
• Given prior to high-fat meal, potential increased
  risk of early post-meal hypoglycemia
• Short duration may provide gaps in insulin supply
  between meals

• Less expensive
• Provides some basal activity which must be taken
  into account if switch to rapid-acting insulin

Roach P. New Insulin Analogues and Routes of
Delivery Pharmacodynamic and Clinical
Considerations. 200847(9)595-610.
20
Rapid Acting vs. Regular insulinBenefits of
Rapid-Acting Insulin

• Rapid-Acting

• Regular

• Smaller increases in blood glucose concentrations
• Lower frequency of hypoglycemia and severe
  hypoglycemia in type 1 diabetes
• Convenience
• Inject right before meal
• Can inject after meal

• Absorbed too slowly to match rate of glucose
  after meals
• Postprandial hyperglycemia
• Inject 30 to 45 minutes prior to meal
• Relatively prolonged duration of action
• Late post-meal hypoglycemia

Roach P. New Insulin Analogues and Routes of
Delivery Pharmacodynamic and Clinical
Considerations. 200847(9)595-610.
21
Short-Acting Insulin Analogs
Aspart
Lispro
Plasma insulin)
Plasma insulin
Regular
Regular
0
30
60
90
120
180
210
150
240
0
50
100
150
200
300
250
Time (min)
Time (min)
Meal SC injection
Meal SC injection
Heinemann, et al. Diabet Med. 199613625629Muda
liar, et al. Diabetes Care. 19992215011506
22
Side effects

• Site irritation
• Local itching and redness
• 10/1394 (0.7)
• Hypoglycemia
• 75-95 of all type 1 report at least one minor
  episode

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Insulin glargine (Lantus)

• First to market
• Similar A1C decreases as NPH
• Decreased hypoglycemic events
• No peak
• Once daily vs bid dosing

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Long-Acting vs. Intermediate Acting

• Glargine
• Flat vs. peak seen with NPH
• Recent studies show may not be completely flat
• Especially at higher doses
• Does not appear to be any overlap or accumulation
• However, gradual increase in activity followed by
  slow decline after long use
• Equal or less patient variability

Roach P. New Insulin Analogues and Routes of
Delivery Pharmacodynamic and Clinical
Considerations. 200847(9)595-610.
25
Glargine vs. NPH

• Glargine does not always provide 24 hour coverage
  in all patients
• 25 of patients may present with rising glucose
  levels the following evening
• Consider twice daily dosing at 12 hour intervals
• Clinical trials glargine vs. NPH
• Less hypoglycemia
• Lower fasting blood glucose
• No difference found in A1c between agents

Roach P. New Insulin Analogues and Routes of
Delivery Pharmacodynamic and Clinical
Considerations. 200847(9)595-610.
26
Glargine vs NPH Insulin
NPH
Glargine
NPH
Plasma insulin
Glargine
0
10
20
30
Time (hr)
Lepore, et al. Diabetes. 199948(suppl 1)A97.
27
Insulin detemir (Levemir)

• Ultra long acting
• Elimination of peak
• Binds to albumin subq and in blood
• Better reproducibility than NPH
• Duration is dose dependent

• Once daily or twice daily dosing
• Decrease risk of wt gain
• Decrease risk of hypoglycemia
• Action is 12-18 hours
• Can you mix?

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Detemir vs. NPH

• Duration of action similar to or slightly longer
  than NPH but shorter than glargine
• 30-50 of patients require twice daily dosing
• Less patient variability
• Possibly smaller peak
• Not well demonstrated in patients with type I
  diabetes
• A clear difference has been shown with insulin
  glargine

Roach P. New Insulin Analogues and Routes of
Delivery Pharmacodynamic and Clinical
Considerations. 200847(9)595-610.
29
Insulin Initiation

• Diabetes is a chronic progressive disease
• Ultimately ends in loss of ß-cell function
• 10 units OR 0.15 units/kg of glargine, NPH or
  detamir at bedtime
• Type 2 patients may require higher doses than
  patients with Type 1 due to resistance
• Increase in insulin by 1 unit may have drastic
  result with type 1 but not effect with type 2
  patient

Mayfield JA., White RD. Insulin Therapy for Type
2 Diabetes Rescue, Augmentation, and Replacement
of Beta Cell Function. American Family Physician.
200470(3)489-500.
30
Insulin Dosing

• Example titration schedule
• Several studies have also shown patient
  involvement in titration is successful
• Increase daily insulin dose by 2 units every 3
  days if fasting glucose was above target
  (72-100mg/dL)

Mean FBG (mg/dL) Weekly Increase in Insulin Dose
100 - lt120 2
120 - lt140 4
140 - lt 180 6
180 8
Barnett A. Dosing of Insulin Glargine in the
Treatment of Type 2 Diabetes. Clinical
Therapeutics. 200729(6)987-999.
31
Insulin Dosing

• If glycemic control remains inadequate with basal
  insulin alone
• Switch to twice daily insulin
• Advancement to basal-bolus insulin
• Initiate bolus insulin at doses of 4 to 10 units
  before the meal with the greatest pre-prandial
  glucose level
• Monitor and titrate to other meals where post
  prandial glucose is not at goal

Barnett A. Dosing of Insulin Glargine in the
Treatment of Type 2 Diabetes. Clinical
Therapeutics. 200729(6)987-999.
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Alternative Insulin Delivery

• Insulin pump
• Composed of a pump reservoir and battery operated
  pump
• Size of beeper
• Canula under the skin
• Change every 2 days
• Set basal rate
• Bolus with meals
• Next goal pump to sense blood glucose and
  administer dose

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Insulin Sensors
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Insulin Pump with Sensor
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Medications affecting glucose

• Increase glucose
• Steroids
• Diuretics
• Estrogens
• HIV medications
• Antipsychotics

• Decrease glucose
• ACE inhibitors
• MAOIs
• Aspirin

Close monitoring of glucose levels and insulin
adjustments will be needed
37
Type 2 (NIDDM)

• Can still produce insulin but inadequately
• Lack of sensitivity to insulin by cells
• Mechanisms
• Insulin resistance (target cells)
• Beta-cell dysfunction (pancreas)

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Pathophysiology of Type 2 Diabetes
Peripheral Tissues (Muscle)
Receptor postreceptor defects
Insulin resistance
Glucose
Liver
Increased glucose production
Pancreas
Impaired insulin secretion
Saltiel AR, Olefsky JM. Diabetes.
1996451661-1669.
39
Risk factors for Type 2

• Genetic component
• Family history confers 2.4 fold risk increase
• Obesity
• Risk doubles for every 20 increase in ideal
  weight
• Ethnic background
• Hispanic gt asiangt african gt caucasian
• History of gestational diabetes
• Increased age

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Risk factors for insulin resistance

• Overweight
• Waist
• gt40 inches in men
• gt35 inches in women
• gt40 yrs of age
• Ethnicity
• Gestational diabetes

• High BP
• High TG
• Low HDL
• Polycystic ovarian disease
• History of type 2 in family

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Diagnosis of Diabetes
A1C FBG (mg/dL) OGTT (mg/dL) Casual
Diabetes 6.5 126 200 test performed 2 hours after 75 g glucose load 200mg/dL AND symptoms of hyperglycemia (polyuria, polydipsia, weight loss)
Pre-Diabetes Impaired fasting glucose (IFG) Impaired glucose tolerance (IGT) 5.7-6.4 100 to 125 N/A N/A 140 to 199 N/A N/A
American Diabetes Association. Standards of
Medical Care in Diabetes-2011. Diabetes Care.
201134(s1)s11-s61.
42
ABCs of Diabetes Care
Parameter ADA Goal
A1c lt7
Preprandial plasma glucose 90-130mg/dL
Postprandial plasma glucose lt180mg/dL
Blood Pressure lt130/80
Cholesterol LDL lt100mg/dL HDL gt40mg/dL (M) gt 50mg/dL (F) TG lt150mg/dL TC lt200mg/dL
American Diabetes Association. Standards of
Medical Care in Diabetes-2011. Diabetes Care.
201134(s1)s11-s61.
43
ADA and ACE glycemic goals
ADA ACE Biochemical Index Normal goal
goal Fasting pre-prandial lt100 90-130
lt110 Post-prandial lt140 lt180
lt140 A1C lt6 lt7 lt6.5
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A1c and Daily Blood Glucose
A1C () Mean plasma glucose (mg/dl)
6 126
7 154
8 183
9 212
10 240
11 269
12 298
Goal HgbA1c lt 7
American Diabetes Association. Standards of
Medical Care in Diabetes-2011. Diabetes Care.
201134(s1)s11-s61.
45
Non-pharmacological therapy
Consistent carbohydrate intake
Monitor blood glucose
Modify fat and calorie content
Optimize BG control
Moderate weight loss
Space meals
Increase physical activity
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Therapy selection in Type 2

• Magnitude of change needed in BG
• Co-existing medical conditions
• Adverse effects
• Contraindication
• Issues with compliance
• Cost to patient and healthcare system

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Mechanisms of action
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Sulfonylureasglyburide (Micronase Diabeta),
glipizide (Glucotrol), glimeperide (Amaryl)

• Mechanism of action
• Primary
• stimulates beta-cell secretion of insulin
  (release)
• Secondary
• decreased rate of hepatic glucose production
• increases insulin receptor sensitivity
• Efficacy
• ? Hgb A1c 1-2
• Common Adverse Events
• Hypoglycemia
• Weight gain
• Rash
• Small chance of cross reactivity with sulfa
  antibiotics

Raskin P. Why insulin sensitizers but not
secretagogues should be retained when initiating
insulin in type 2 diabetes. Diabetes Metab Res
Rev. 2008243-13.
49
Sulfonylureas

• Hypoglycemia
• Older adults have a 36 ? risk
• Risk factors
• Age-related decline in renal function
• Co-administration with insulin sensitizers
• Recent discharge from hospital
• gt60 years
• Caloric restriction
• Use of 5 or more medications

Neumiller JJ, Setter SM. Pharmacologic Management
of the Older Patient with Type 2 Diabetes
Mellitus. The American Journal of Geriatric
Pharmacotherapy. 20097(6)324-342.
50
Sulfonylureas

• Place in therapy
• 75-90 initial response, failure over time due to
  loss of beta cells
• 25 complete responders, do not require
  additional agent
• Require functioning ß-cells to work
• May be ineffective in long term diabetes
• Combination with insulin not as effective as with
  metformin
• Alternative to insulin therapy (as monotherapy or
  additon to metformin)

Raskin P. Why insulin sensitizers but not
secretagogues should be retained when initiating
insulin in type 2 diabetes. Diabetes Metab Res
Rev. 2008243-13.
51
Metformin (Glucophage)

• Mechanism of action
• Primary
• inhibits hepatic glucose production
• Secondary
• increases insulin sensitivity, enhancing
  peripheral utilization of glucose
• Efficacy
• ? Hgb A1c 1-2
• Common Adverse Events
• GI side effects most common
• Typically transient
• Weight loss

Glucophage package insert. Princeton, NJ
Bristol-Myers Squibb Company 2009.
52
Metformin

• B-12 deficiency
• Up to 22 of patients with type 2 diabetes
• Often not clinically significant
• May need to supplement with B-12
• Calcium supplementation may reverse
• Higher doses (gt1g/day) and duration (gt3 years) of
  therapy increase risk

Vidal-Alaball J and Butler CC. Reduced serum
vitamin B-12 in patients taking metformin. BMJ
20103402198.
53
Metformin

• Precautions/Contraindications
• Renal disease or dysfunction
• Serum creatinine 1.5 in men 1.4 in women
• Acute or chronic metabolic acidosis
• IV dye studies
• stop metformin day of study and do not resume
  until renal function returns to normal, usually
  48 hours
• Age gt 80 years
• Impaired hepatic function
• Excessive alcohol use
• Medical condition that may predispose to
  metabolic or lactic acidosis or hypoxemia
• COPD, PVD, infections, surgery, CHF

Glucophage package insert. Princeton, NJ
Bristol-Myers Squibb Company 2009.
54
Metformin

• Lactic Acidosis
• Meta-analysis assessed incidence of fatal and
  non-fatal lactic acidosis
• Type 2 metformin treated patients vs.
  non-metformin treated patients
• no cases of lactic acidosis in 70,490
  patient-years of metformin use vs. 55,451
  patient-years in non-metformin group
• No evidence that metformin is associated with an
  increased risk of lactic acidosis

Salpeter SR, Greyber E, Pasternak GA, et al. Risk
of fatal and nonfatal lactic acidosis with
metformin use in type 2 diabetes mellitus.
Cochrane Database Syst Rev. 2010. Apr 14(4).
55
Metformin

• Place in therapy
• First line agent
• Only agent shown to decrease macrovascular
  complications
• Hypoglycemia rare when used as monotherapy
• Monotherapy or in combination with other oral
  agents and insulin

American Diabetes Association. Standards of
Medical Care in Diabetes-2011. Diabetes Care.
201134(s1)s11-s61.
56
Glinidesrepaglinide (Prandin), nateglinide
(Starlix)

• Mechanism of action
• stimulates release of insulin from beta-cells
• Bind to a different receptor than sulfonylureas
• Glucose Dependent, unlike sulfonylureas
• Do not stimulate insulin secretion in absence of
  hyperglycemia
• Very short duration of action
• Efficacy
• ? Hgb A1c 0.5-1.5
• Common Adverse Events
• Hypoglycemia (greater than sulfonylurea)
• Weight gain

Campbell RK. Type 2 diabetes Where we are today
An overview of disease burden, current
treatments, and treatment strategies. JAPhA.
Sept/Oct 2009.s3-s9. .
57
Glinides

• Place in Therapy
• High post-prandial glucose levels
• Take (0-30 minutes) before meals
• Skip a meal, skip the dose
• Useful in irregular meal pattern
• elderly
• Useful if prone to hypoglycemia
• Expensive

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Thiazolidinedionesrosiglitazone (Avandia),
pioglitazone (Actos)

• Mechanism of action
• Primary
• Enhances peripheral uptake of glucose by
  increasing glucose/insulin receptors
• Enhance insulin sensitivity
• Secondary
• Reduces hepatic glucose production
• Efficacy
• ? Hgb A1c 0.5-0.8
• Common Adverse Events
• Edema
• Weight gain

Campbell RK. Type 2 diabetes Where we are today
An overview of disease burden, current
treatments, and treatment strategies. JAPhA.
Sept/Oct 2009.s3-s9.
59
ThiazolidinedionesEffects on Cholesterol

• LDL particle size
• Small dense more closely associated with CHD
• pioglitazone found to increase LDL size
• Reduces Triglycerides
• pioglitazone gt rosiglitazone
• Pio ?10-20
• Rosi neutral to slight reduction
• Increasing HDL
• Both increase by 3-9mg/dL
• Newer evidence suggests pioglitazone gt
  rosiglitazone

Rizzo M, Emanuel RC, Rini GB, et al. The
differential effects of thiazolidindiones on
atherogenic dyslipidemia in type 2 diabetes what
is the clinical significance?
60
Thiazolidinedione Prescribing Considerations

• Contraindications
• Contraindicated in patients with NYHA Class III
  or IV heart failure
• Warning and Precautions
• CHF
• Edema
• Hepatic
• Fractures
• Increased incidence found in females
• Hypoglycemia
• Macular edema

Actospackage insert. Deerfield, IL Takeda
Pharmaceutical America, Inc 2011.
61
Cardiovascular Risk

• Data suggests that Rosiglitazone may increase
  risk of cardiovascular events
• Pioglitazone does not appear to have the same
  risk
• Meta-analysis of 16 observational studies
• Included 810,000 thiazolidinedione users
• Compared to pioglitazone, rosiglitazone was
  associated with a statistically significant
  increased risk of CHF, MI, death

Loke, YK, Kwok CS, Singh S. Comparative
cardiovascular effects of thiazolidinediones
systematic review and meta-analysis of
observational studies. BMJ.2011342d1309.
62
Thiazolidinediones

• Place in therapy
• Losing place in therapy, no longer considered a
  first line class
• Maximum effect can take up to 8 weeks
• Expensive
• Recommend pioglitazone vs. rosiglitazone due to
  safety concerns

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Alpha-glucosidase inhibitorsacarbose
(Precose), miglitol (Glycet)

• Mechanism of action
• inhibits enzyme that hydrolyzes complex starches
  and sugars into readily absorbable molecules,
  delaying absorption of glucose
• If hypoglycemic reaction need glucose source (not
  sucrose)
• Efficacy
• ? Hgb A1c 0.5-0.8
• Common Adverse Events
• GI intolerance, cramping, flatulence
• titrate dose slowly
• minimize carbohydrate intake at first
• may resolve in 8-12 weeks as gut receptors adjust

Campbell RK. Type 2 diabetes Where we are today
An overview of disease burden, current
treatments, and treatment strategies. JAPhA.
Sept/Oct 2009.s3-s9.
64
Alpha-glucosidase inhibitors

• Place in therapy
• for high post-prandial blood glucose
• few drug interactions
• hypoglycemia rare in monotherapy
• does not cause weight gain
• Do not use in patients with inflammatory bowel
  disease or conditions with risk of bowel
  perforation

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Combination Therapy

• Glucovance
• Glyburide/metformin
• Avandamet
• Rosiglitazone/metformin
• Metaglip
• Glipizide/metformin

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Pramlintide (Symlin)

• Synthetic analog of human amylin
• Amylin hormone synthesized by beta-cell
• Reduce post-prandial blood sugar
• Reduce glucose fluctuations
• Lower meal-time insulin requirements
• Lower insulin by ½ when starting
• Injectable three times a day before meals
• Side effects nausea primarily

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Pramlintide

• Do not use in the following patients
• Diagnosis of gastroparesis
• Hypoglycemia unawareness
• Poor compliance with insulin or self-blood
  glucose monitoring
• HgbA1c gt9
• Recurrent, severe hypoglycemia requiring
  assistance during the past 6 months
• Require use of medications that stimulate
  gastrointestinal motility
• Pediatric patients

Symlin package insert. San Diego, CA Amylin
Pharmaceuticals, Inc. 2008.
69
Pramlintide specifics

• Injectable- insulin syringe
• Starting dose Type 1 DM 15 mcg (2.5 units)
• Starting dose Type 2 DM 60 mcg (10 units)
• Titrate as tolerated every 3 days
• Symlin pens (60 and 120 mcg)
• Use at the time of a meal (250 cal)
• Separate injection from insulin
• Decrease dose of prandial insulin by 50
• Potentially less nausea than with exenatide

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Incretin mimetics

• New class of antihyperglycemics
• Incretin hormone (GLP-1) stimulates glucose
  dependent insulin secretion and slows GI motility
• GLP-1 levels are decreased in diabetics
• Agents
• Exenatide (Byetta)
• Liraglutide (Victoza)
• Tasoglutide (R1583) phase III trials

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Exenatide (Byetta)

• Gila monster saliva
• MOA
• Role in adjunct therapy
• Dosing
• Side effects
• Weight reduction benefit

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Liraglutide (Victoza)

• FDA approved 2010
• Similar to Byetta
• Once daily instead of twice
• Weight reduction benefit
• Dosing
• Side effects

74
Comparing GLP-1 Analog
Exenatide Liraglutide
Dosing Twice daily Once daily
Efficacy ?in A1C of 1 (Ranges in studies 0.4-1) 1-1.5
Weight Reduction 2-3kg 3-4kg not significantly different vs. exenatide
Nausea 57 10-15 (often described as mild) Overall, significantly fewer adverse events vs. exenatide
Boxed Warnings No boxed warning Causes thyroid C-cell tumors at clinically relevant exposures in rodents
Dosage adjustments CrCl 30-50 mL/min Use caution when initiating or escalating doses. CrCl lt30 mL/min Not recommended. No dosage adjustments use with caution due to insufficient studies in this population
Grossman S. Differing Incretin Therapies Based on
Structure, Activity, and Metabolism Focus on
Liraglutide. Pharmacotherapy.20092925s-32s.
75
Exenatide and Liraglutide

• Place in therapy
• Not recommended as first line therapy for
  patients inadequately controlled on diet and
  exercise
• Not for treatment of type 1 diabetes
• Not indicated in combination with insulin
• Some endocrinologists use
• May use as adjunctive therapy with oral agents
• May be useful in patients who are overweight

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DPP-4 Inhibitors

• DPP-4 quickly inactivates GLP-1
• Oral agents
• Agents
• Saxagliptin (Onglyza)
• Sitagliptin (Januvia)
• Linaglitpin (Tradjenta)

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Sitagliptin Januvia Saxagliptin Onglyza Linaglitpin Tradjenta
Efficacy Monotherapy ? A1C 0.36 to 0.76 With metformin ? A1C 0.7 With pioglitazone ? A1C 0.85 With glimepiride ? A1C 0.45 Monotherapy ? A1C 0.43 to 0.54 With metformin ? A1C 0.6 to 0.7 With thiazolidinedion ? A1C 0.9 With glyburide ? A1C 0.6 Monotherapy ? A1C 0.44 to 0.50 With metformin ? A1C 0.48 to 0.49 With thiazolidinedione ? A1C 1.06
Renal Dosage Adjustments Normal dose 100mg PO daily CrCl 30-50 ml/min 50mg daily CrCl lt 30 ml/min 25mg daily Normal dose 2.5 to 5 mg PO daily CrCl 50ml/min 2.5mg daily No dose adjustment necessary
Drug Interactions Limited metabolism through CYP 3A4 2C8 no dosage recommendations Metabolized by CYP3A4 warning placed to reduce dose if 3A4 inhibitors are used Substrate for CYP3A4 weak competitive inhibitor of 3A4 efficacy may be reduced if combined with 3A4 inducors
Neumiller JJ, Wood L, Campbell RK. Dipeptidyl
Peptidase-4 Inhibitors for the Treatment of Type
2 Diabetes Mellitus. Pharmacotherapy.2010.
30(5)464-484. Scott LJ. Linagliptin In type 2
Diabetes Mellitus. Drugs 201171(5)611-624.
79
DPP-IV Inhibitorssitagliptin, saxagliptin,
linaglitpin

• Place in therapy
• Tolerable side effect profile
• Considered weight neutral, hypoglycemia rare
• Often similar to placebo group in clinical trials
• Add on therapy to first line oral hypoglycemic
  agents
• Special populations sensitive to hypoglycemia
• Older adults

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Canagliflozin (Invokana)

• Approved for treatment of adults with type 2
  Diabetes in conjunction with lifestyle
  interventions
• Initiate at 100 mg PO daily, before first meal of
  the day
• Can increase to 300 mg PO daily if eGFR 60
  mL/min (if less max dose 100 mg/day)
• Contraindicated with hypersensitivity, ESRD,
  dialysis
• Avoid or discontinue if eGFR lt 45 mL/min
• Additional Warnings include
• Hypotension, hyperkalemia, hypoglycemia, mycotic
  genital infections, and increased LDL cholesterol

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Invokana cont.

• Significant Interactions
• Rifampin (UGT inducers)
• 50 decrease in AUC
• Increased digoxin Cmax and AUC
• Pharmacokinetics
• 65 absorption
• 99 protein bound in plasma
• O-glucuronidation via UGT1A9 and UGT2B4 to
  inactive metabolites
• 33 excreted in urine
• 40 excreted unchanged in feces

• Common Adverse Events ( 5)
• Urinary track infections (UTIs)
• Mycotic genital infections
• Increased frequency and/or volume of urination
  and nocturia
• Less common include
• Hypersensitivity reaction
• Constipation
• Thirst
• Nausea and abdominal pain

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Complications and co-morbid conditions

• Microvascular
• Diabetic nephropathy
• 30 progress to end stage
• Diabetic retinopathy
• 20-25 in type 1 diabetes
• Close assoc with nephropathy
• Diabetic neuropathy
• Two major categories

• Macrovascular
• CVD
• Accounts for 70 of deaths in type 2

86
Microvascular Complications

• Nephropathy
• Retinopathy
• Neuropathy
• Foot ulcers/lesions
• Numbness, pain
• Sexual dysfunction
• Gastroparesis

87
Macrovascular Complications

• Cardiovascular Diseases (CVD)
• Coronary Artery Disease (CAD)
• Myocardial Infarction (MI)
• Stroke or transient ischemic attack (TIA)
• Peripheral Artery Disease (PAD)

88
Gestational diabetes

• Approx. 7 of pregnant women develop
• Defined at high BG during pregnancy
• All women some degree of glucose intolerance
• Placenta hormones mothers pancreas usually
  compensates
• Diagnosis

89
Risk factors

• Obesity prior to pregnancy
• Ethnic group
• Glucose in urine
• Family history of diabetes
• Previous birth of baby gt9lbs
• Previous birth of stillborn
• Gestational diabetes in previous pregnancy
• Too much amniotic fluid

90
Management of gestational diabetes

• Monitor BG 4x day
• Urine ketone monitor
• Dietary changes
• Exercising
• Insulin

91
References

• American Diabetes Association (ADA) Professional
  Practice Committee. Standards of medical care in
  diabetes - 2013. Diabetes Care. 201336(1)
  S11-S66.
• Centers for Disease Control and Prevention.
  Diabetes Report Card 2012. Atlanta, GA Centers
  for Disease Control and Prevention, US Department
  of Health and Human Services 2012. Available
  at www.cdc.gov/diabetes/pubs/pdf/DiabetesReportCa
  rd.pdf
• Centers for Disease Control and Prevention.
  National Diabetes Fact Sheet, 2011. Atlanta, GA
  Centers for Disease Control and Prevention, US
  Department of Health and Human Services 2011.
  Available at http//www.cdc.gov/diabetes/pubs/pdf
  /ndfs_2011.pdf.
• Diabetes Surveillance Report, Maine 2012.
  Augusta, ME Diabetes Prevention and Control
  Program, Maine Center for Disease Control and
  Prevention 2012. Available at
  http//www.maine.gov/dhhs/mecdc/population-health/
  dcp/statistics.htm
• Maine Center for Disease Control and Prevention.
  Maine Diabetes Prevention and Control Program,
  Health Fact Sheet Diabetes in Maine. Maine
  Center for Disease Control and Prevention, Maine
  Department of Health and Human Services 2011.
• Inzucchi SE, Bergenstal RM, Buse JB, et al.
  Management of hyperglycemia in type 2 diabetes a
  patient-centered approach, Position Statement by
  the American Diabetes Association (ADA) and the
  European Association for the Study of Diabetes
  (EASD). Diabetes Care. 2012351364-79.
• Invokana (package insert). Janssen
  Pharmaceuticals, Inc. Titusville, NJ. March
  2013 http//www.invokanahcp.com/. Accessed
  08/28/13.
• Stratton IM, Adler AI, Neil HAW, et al.
  Association of glycaemia with macrovascular and
  microvascular complications of type 2 diabetes
  (UKPDS 35) prospective observational study.
  BMJ. 2000321405-12.
• The Action to Control Cardiovascular Risk in
  Diabetes (ACCORD) Study Group. Effects of
  intensive glucose lowering in type 2 diabetes.
  NEJM. 2008358(24)2545-59.

92
References

• Duckworth W, Abraira C, Moritz T, et al. Glucose
  control and vascular complications in veterans
  with type 2 diabetes. NEJM. 2009360(2)129-39.
  
• Ray KK, Kondapally Seshasai S, Wijesuriya S, et
  al. Effect of intensive control of glucose on
  cardiovascular outcomes and death in patients
  with diabetes mellitus a meta-analysis of
  randomised controlled trials. Lancet.
  20093731765-72.
• Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi
  M, et al. Effect of intensive glucose lowering
  treatment on all cause mortality, cardiovascular
  death, and microvascular events in type 2
  diabetes a meta-analysis of randomised control
  trials. BMJ. 2011343d4169 doi10.1136/bmj.d416
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• Hemmingsen B, Lund SS, Gluud C, et al. Intensive
  glycaemic control for patients with type 2
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  trials. BMJ. 2011343d6898 Doi
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• Ismail-Beigi F, Moghissi E, Tiktin M, et al.
  Individualizing glycemic targets in type 2
  diabetes mellitis implications of recent
  clinical trials. Ann Intern Med.
  2011154554-9.
• Bennett WL, Maruthur NM, Singh S, et al.
  Comparative effectiveness and safety of
  medications for type 2 diabetes an update
  including new drugs and 2-drug combinations. Ann
  Intern Med. 2011154602-13.
• Matthews JE, Stewart MW, De Boever EH, et al.
  Pharmacodynamics, pharmacokinetics, safety, and
  tolerability of albiglutide, a long-acting
  glucagon-like peptide-1 mimetic, in patients with
  type 2 diabetes. J Clin Endocrinol Metab.
  2008934810-4817.
• Garber AJ, King AB, Del Prato SD, et al. Insulin
  degludec, an ultra-longacting basal insulin,
  versus insulin glargine in basal-bolus treatment
  with mealtime insulin aspart in type 2 diabetes
  (BEGIN Basal-Bolus Type 2) a phase 3,
  randomized, open-label, treat-to-target
  non-inferiority trial. Lancet.
  20123791498-507.
• Nisly SA, Kolanczyk DM, and Walton AM.
  Canagliflozin, a new sodium glucose
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• Tucker ME. FDA rejects Novo Nordisks Insulin
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