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
This online program is available until December 31, 2016
In order to receive contact hours, you must:
1) Listen to entire program
2) Complete the post-test and the evaluation
3) Once you have submitted your evaluation, you will then be sent
your certificate of completion.
Thank you!
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.
DIABETES
Deb Boles, MS,RPh
Clinical Pharmacy Specialist
Objectives
Distinguish the three types of known
diabetes
Discuss the different types of insulin
including new therapies
List potential therapies for type 2 diabetes
Diabetes impact
Effects 15 million americans (8% of the
population)
3rd leading cause of death behind cancer
Estimated 12 million people have it and
don’t know it
Incidence of Diabetes in the US
Centers For Disease Control and Prevention. Diabetes Data and Trends.
.http://apps.nccd.cdc.gov/DDT_STRS2/NationalDiabetesPrevalenceEstimates.aspx?mode=DBT
Glucose and Insulin Production
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
3 Major Classifications of Diabetes
Cause
Incidence
Type 1
Auto-immune mediated
destruction of insulinproducing 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 3-5% of pregnancies
pregnancy; increases risk
for type 2 diabetes later in
life
Type 1 (IDDM)
Only accounts for 510% of all cases
Strong genetic
component
Environmental trigger
Insulin dependent
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
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
History of insulin
For decades – only
animal source
1980’s recombinant
technology
Utilizes E. Coli
Insulin producing
genes
Insulin Properties
Type of Insulin
Rapid Acting
Aspart (Novolog®)
Lispro (Humalog®)
Glulisine (Apidra®)
Short Acting
Regular
Onset
Peak
Duration
15-30 minutes
90 minutes
3-5
3-5
3-5
30-60 minutes
2-3 hours
6-10
2-3 hours
4-10 hours
12-18 hours
Intermediate Acting
NPH
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. 2008;47(9):595-610.
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
Insulin glulisine (Apridra)
Two amino acid
changes
Bind to Insulin
receptors affecting
glucose transfer across
cells
12 week study
premeal versus
postmeal
Insulin aspart (Novolog)
Single amino acid
change
Glucose lowering
effects better than
regular
Better post-prandial
control
Comparable to lispro
Rapid acting mixes
Rapid acting can’t be
mixed with NPH
Mixes are plain with
protamine bound
product
Lispro 25/75 or 50/50
Aspart 30/70 or 50/50
Rapid Acting vs. Regular insulin
Benefits of Regular Insulin
Rapid-Acting
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
Regular
Less expensive
Provides some basal activity
which must be taken into
account if switch to rapidacting insulin
Roach P. New Insulin Analogues and Routes of Delivery; Pharmacodynamic and Clinical
Considerations. 2008;47(9):595-610.
Rapid Acting vs. Regular insulin
Benefits of Rapid-Acting Insulin
Rapid-Acting
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
Regular
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. 2008;47(9):595-610.
Short-Acting Insulin Analogs
Aspart
Regular
Plasma insulin
Plasma insulin)
Lispro
Regular
0
30 60 90 120 150 180 210 240
0
50
Time (min)
Meal
SC injection
100 150
200
250
300
Time (min)
Meal
SC injection
Heinemann, et al. Diabet Med. 1996;13:625–629;Mudaliar, et al. Diabetes Care. 1999;22:1501–
1506
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
Insulin glargine (Lantus)
First to market
Similar A1C decreases
as NPH
Decreased
hypoglycemic events
No peak
Once daily vs bid
dosing
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. 2008;47(9):595-610.
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. 2008;47(9):595-610.
Glargine vs NPH Insulin
Plasma insulin
NPH
Glargine
NPH
Glargine
0
10
20
Time (hr)
Lepore, et al. Diabetes. 1999;48(suppl 1):A97.
30
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?
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. 2008;47(9):595-610.
Insulin Initiation
Diabetes is a chronic progressive disease
Ultimately ends in loss of β-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. 2004;70(3):489-
Insulin Dosing
Example titration schedule
Mean FBG (mg/dL)
Weekly Increase in Insulin Dose
≥100 - <120
2
≥ 120 - <140
4
≥ 140 - < 180
6
≥180
8
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)
Barnett A. Dosing of Insulin Glargine in the Treatment of Type 2 Diabetes. Clinical Therapeutics.
2007;29(6):987-999.
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.
2007;29(6):987-999.
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
Insulin Sensors
Insulin Pump with Sensor
Medications affecting glucose
Increase glucose
Steroids
Diuretics
Estrogens
HIV medications
Antipsychotics
Decrease glucose
ACE inhibitors
MAOI’s
Aspirin
Close monitoring of glucose levels and insulin
adjustments will be needed
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)
Pathophysiology of Type 2 Diabetes
Peripheral Tissues
(Muscle)
Receptor +
postreceptor defects
Glucose
Liver
Increased glucose
production
Pancreas
Impaired insulin
secretion
Saltiel AR, Olefsky JM. Diabetes. 1996;45:1661-1669.
Insulin
resistance
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 > asian> african > caucasian
History of gestational diabetes
Increased age
Risk factors for insulin resistance
Overweight
Waist
>40 inches in men
>35 inches in women
>40 yrs of age
Ethnicity
Gestational diabetes
High BP
High TG
Low HDL
Polycystic ovarian
disease
History of type 2 in
family
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)
5.7%-6.4%
100 to 125
N/A
N/A
N/A
140 to 199
N/A
Impaired glucose
tolerance (IGT)
American Diabetes Association. Standards of Medical Care in Diabetes-2011. Diabetes Care.
2011;34(s1):s11-s61.
ABCs of Diabetes Care
Parameter
ADA Goal
A1c
<7%
Preprandial plasma
glucose
90-130mg/dL
Postprandial plasma
glucose
<180mg/dL
Blood Pressure
<130/80
Cholesterol
LDL <100mg/dL
HDL >40mg/dL (M)
> 50mg/dL (F)
TG <150mg/dL
TC <200mg/dL
American Diabetes Association. Standards of Medical Care in Diabetes-2011. Diabetes Care.
2011;34(s1):s11-s61.
ADA and ACE glycemic goals
Biochemical Index
Normal
ADA
ACE
goal
goal
Fasting pre-prandial <100
90-130 <110
Post-prandial
<140
<180
<140
A1C
<6
<7
<6.5
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 < 7%
American Diabetes Association. Standards of Medical Care in Diabetes-2011. Diabetes Care.
2011;34(s1):s11-s61.
Non-pharmacological therapy
Consistent carbohydrate intake
Monitor blood glucose
Optimize BG control
Modify fat and
calorie content
Moderate weight loss
Space meals
Increase physical activity
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
Mechanisms of action
Sulfonylureas
glyburide (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. 2008;24:3-13.
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
>60 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. 2009;7(6):324-342.
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 β-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. 2008;24:3-13.
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.
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 (>1g/day) and duration (>3 years) of
therapy increase risk
Vidal-Alaball J and Butler CC. Reduced serum vitamin B-12 in patients taking metformin. BMJ;
2010;340:2198.
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 > 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.
Metformin
Lactic Acidosis
Meta-analysis assessed incidence of fatal and nonfatal lactic acidosis
Type 2 metformin treated patients vs. nonmetformin 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).
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.
2011;34(s1):s11-s61.
Glinides
repaglinide (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.
.
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
Thiazolidinediones
rosiglitazone (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.
Thiazolidinediones
Effects on Cholesterol
LDL particle size
Small dense more closely associated with CHD
pioglitazone found to increase LDL size
Reduces Triglycerides
pioglitazone > rosiglitazone
Pio ↓10-20%
Rosi neutral to slight reduction
Increasing HDL
Both increase by 3-9mg/dL
Newer evidence suggests pioglitazone > 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?
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
Actos[package insert]. Deerfield, IL: Takeda Pharmaceutical America, Inc; 2011.
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.2011;342:d1309.
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
Alpha-glucosidase inhibitors
acarbose (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.
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
Combination Therapy
Glucovance
Glyburide/metformin
Avandamet
Rosiglitazone/metformin
Metaglip
Glipizide/metformin
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
Pramlintide
Do not use in the following patients:
Diagnosis of gastroparesis
Hypoglycemia unawareness
Poor compliance with insulin or self-blood glucose
monitoring
HgbA1c >9%
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.
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
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
Exenatide (Byetta)
Gila monster saliva
MOA
Role in adjunct
therapy
Dosing
Side effects
Weight reduction
benefit
Liraglutide (Victoza)
FDA approved 2010
Similar to Byetta
Once daily instead of
twice
Weight reduction
benefit
Dosing
Side effects
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 <30 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.2009;29:25s-32s.
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
DPP-4 Inhibitors
DPP-4 quickly
inactivates GLP-1
Oral agents
Agents
Saxagliptin (Onglyza)
Sitagliptin (Januvia)
Linaglitpin (Tradjenta)
Sitagliptin
Januvia®
Efficacy
Renal Dosage
Adjustments
Drug
Interactions
Saxagliptin
Onglyza™
Linaglitpin
Tradjenta™
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%
Normal dose 100mg PO daily:
CrCl 30-50 ml/min 50mg daily
CrCl < 30 ml/min 25mg daily
Normal dose 2.5 to 5 mg PO
daily:
CrCl ≤50ml/min 2.5mg daily
No dose adjustment
necessary
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 2011;71(5):611-624.
DPP-IV Inhibitors
sitagliptin, 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
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 < 45 mL/min
Additional Warnings include:
Hypotension, hyperkalemia, hypoglycemia, mycotic genital
infections, and increased LDL cholesterol
Invokana cont.
Significant Interactions
Rifampin (UGT inducers)
~50% decrease in AUC
Increased digoxin Cmax and
AUC
Pharmacokinetics
~ 65% absorption
Common Adverse Events ( ≥
5%)
Urinary track infections (UTIs)
Mycotic genital infections
Increased frequency and/or volume
of urination and nocturia
Less common include:
~99% protein bound in plasma
Hypersensitivity reaction
O-glucuronidation via UGT1A9
and UGT2B4 to inactive
metabolites
Constipation
~33% excreted in urine
~ 40 excreted unchanged in
feces
Thirst
Nausea and abdominal pain
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
Microvascular Complications
Nephropathy
Retinopathy
Neuropathy
Foot ulcers/lesions
Numbness, pain
Sexual dysfunction
Gastroparesis
Macrovascular Complications
Cardiovascular Diseases (CVD)
Coronary Artery Disease (CAD)
Myocardial Infarction (MI)
Stroke or transient ischemic attack (TIA)
Peripheral Artery Disease (PAD)
Gestational diabetes
Approx. 7% of pregnant women develop
Defined at high BG during pregnancy
All women some degree of glucose
intolerance
Placenta hormones – mother’s pancreas
usually compensates
Diagnosis
Risk factors
Obesity prior to pregnancy
Ethnic group
Glucose in urine
Family history of diabetes
Previous birth of baby >9lbs
Previous birth of stillborn
Gestational diabetes in previous pregnancy
Too much amniotic fluid
Management of gestational
diabetes
Monitor BG 4x day
Urine ketone monitor
Dietary changes
Exercising
Insulin
References:
American Diabetes Association (ADA) Professional Practice Committee. Standards of medical care in diabetes 2013. Diabetes Care. 2013;36(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/DiabetesReportCard.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. 2012;35:1364-79.
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. 2000;321:405-12.
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group. Effects of intensive glucose
lowering in type 2 diabetes. NEJM. 2008;358(24):2545-59.
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diabetes. NEJM. 2009;360(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.
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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
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Hemmingsen B, Lund SS, Gluud C, et al. Intensive glycaemic control for patients with type 2 diabetes: systemic
review with meta analysis and trial sequence analysis of randomised clinical trials. BMJ. 2011;343:d6898 Doi:
10.1136/bmj.d6898.
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. 2011;154:554-9.
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. 2011;154:602-13.
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.
2008;93:4810-4817.
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. 2012;379:1498-507.
Nisly SA, Kolanczyk DM, and Walton AM. Canagliflozin, a new sodium – glucose cotransporter 2 inhibitor, in the
treatment of diabetes. Am J Health-Syst Pharm. 2013;70:311-9.
Tucker ME. FDA rejects Novo Nordisk’s Insulin Degludec. Medscape News. Accessed February 12, 2013.
Available at: http://www.medscape.com/viewarticle/779077
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