This is part two of the diabetes presentation aimed for pharmacists and allied health professional who are interested in tailoring special pharmaceutical care plans for diabetic patients.

1. Week
Diabetes Mellitus
2
Part 2
Anas Bahnassi PhD CDM CDE

2. Oral hypoglycemic agents sites of action
PANCREAS
MUSCLE
LIVER
ADIPOSE TISSUE
INSULIN Secretion
GLUCOSE PRODUCTION
Biguanides
Thiazolidinediones
Sulfonylureas
Meglitinides
Insulin
Amylin
PERIPHERAL
GLUCOSE UPTAKE
Thiazolidinediones
(Biguanides)
INTESTINE
GLUCOSE ABSORPTION
α- glucosidase inhibitors
INTESTINAL HORMONES
Incretin

3. α-Glucosidase inhibitors
Drug
Typical dosing
Acarbose
25–100 mg with first bite
(Precose) 25, of each meal.
50, 100 mg Begin with 25 mg; ↑ by
25 mg/meal every 4–8
weeks.
Min and Max Mean
daily dose
t1/2
Minimum: 25 2.8 hr
mg TID;
Maximum
dose is 50 mg
TID if ≤60 kg;
100 mg TID if
>60 kg.
Miglitol
25–100 mg with first bite Minimum: 25
2 hr
(Glyset) 25, of each meal.
mg TID
50, 100 mg Begin with 25 mg; ↑ by Maximum: 100
25 mg/meal every 4–8 mg TID
weeks.
Duration of
Activity
Bioavailability ,
Metabolism, and
Excretion
Comments
Affects absorption
of complex
carbohydrates in a
single meal
F = 0.5%–1.7%;
Titrate doses
extensively metabolized slowly to avoid
by GI amylases to
GI effects
inactive products; 50%
excreted unchanged in
the feces
Affects absorption
of complex
carbohydrates in a
single meal
Dose of 25 mg is
completely absorbed;
dose of 100 mg 50–70%
absorbed; elimination by
renal excretion as
unchanged drug

4. Biguanides
Drug
Typical dosing
Min and Max
daily dose
Mean t1/2
Duration of Bioavailability ,
Activity
Metabolism, and
Excretion
Metformin
(Glucophage) 500,
850, 1000 mg; 500
mg/mL liquid
Begin with 500 mg 0.5–2.5 g BID Plasma, 6.2 hr
QD or /BID; ↑ by
or TID
Whole blood,
500 mg QD every
17.6 hr
1–2 weeks.
6–12 hr
Metformin
extended-release
(Glucophage XR)
500, 750, 1000 mg
500–1,000 mg/QD 1,500–2,000 Active drug is 24 hr
with evening
mg QD
released
meal; ↑ by 500
slowly
mg every 1–2
weeks.
F = 50%–60%;
excreted
unchanged in
urine
Comments
Take with food. Avoid
in patients with renal
dysfunction or those
who could be
predisposed to lactic
acidosis (e.g.,
alcoholism, CHF, severe
respiratory disorders,
liver failure)

5. Nonsulfonylurea Insulin Secretagogues (Glinides)
Drug
Typical dosing
Repaglinide If HbA1c is <8% or if this is
(Prandin) 0.5, first drug, begin with 0.5
1, 2 mg
mg with each meal. For
others, begin with 1–2
mg/meal.
Nateglinide
(Starlix) 60,
120 mg
Min and Max Mean
daily dose
t1/2
0.5–4 mg with
each meal (16
mg/day)/TID–
QID
120 mg TID 1–30 min
60 or 120 mg
before meals; 60 mg TID for TID
patients with near-normal
HbA1c at initiation.
Duration of
Activity
1 hr Cmax is at 1 hr;
duration is
approximately
2–3 hr
Bioavailability ,
Metabolism, and
Excretion
Comments
F = 56%; 92%
Take only with
metabolized to inactive meals. Skip dose if
products by the liver; meal is skipped.
8% excreted as
Maximum dose per
metabolites unchanged meal is 4 mg.
in the urine
1.5 hr Onset, 20 min; F = 73%; metabolized to Skip dose if meal is
peak, 1 hr;
inactive products
skipped.
duration, 2–4 (predominantly) that
hr
are excreted in the urine
(83%) and feces (10%)

6. Thiazolidinediones
Drug
Typical dosing
Min and Mean t1/2 Duration of
Bioavailability ,
Max
Activity
Metabolism, and
daily
Excretion
dose
Rosiglitazone 4 mg QD; ↑ to 8 4–8 mg 3–4 hr Onset and
F = 99%; extensively
(Avandia) 2, 4, mg QD (or 4 mg
daily in
duration poorly metabolized in liver
8 mg
BID)
single or
correlated with into inactive
divided
half-life because metabolites; excreted
doses
of mechanism of 2/3 in urine and 1/3
action. Onset at in feces
3 weeks; max at
Pioglitazone 15–30 mg QD; ↑ 15–45 3–7 hr ≥4 weeks. Offset Extensively
(Actos) 15, 30, to 45 mg QD. If
mg QD (16–24 hr likely to be
metabolized in liver;
45 mg
used with insulin,
for all
similar
15%–30% excreted in
↓ insulin dose by
metabolit
urine, remainder
10%–25% once FPG
es)
eliminated in
<120 mg/dL.
the feces
Comments
Food has no effect on
absorption. BID dosing may
have greater HbA1c lowering
effect. No dose adjustments
required in renal failure. Avoid
in patients with liver disease
and heart failure.
Food delays absorption but is
not clinically significant. No
dose adjustments required in
renal disease. Avoid in patients
with liver disease and heart
failure.

7. Nonsulfonylurea Insulin Secretagogues (Glinides)
Drug
Typical dosing
Repaglinide If HbA1c is <8% or if this is
(Prandin) 0.5, first drug, begin with 0.5
1, 2 mg
mg with each meal. For
others, begin with 1–2
mg/meal.
Nateglinide
(Starlix) 60,
120 mg
Min and Max Mean
daily dose
t1/2
0.5–4 mg with
each meal (16
mg/day)/TID–
QID
120 mg TID 1–30 min
60 or 120 mg
before meals; 60 mg TID for TID
patients with near-normal
HbA1c at initiation.
Duration of
Activity
1 hr Cmax is at 1 hr;
duration is
approximately
2–3 hr
Bioavailability ,
Metabolism, and
Excretion
Comments
F = 56%; 92%
Take only with
metabolized to inactive meals. Skip dose if
products by the liver; meal is skipped.
8% excreted as
Maximum dose per
metabolites unchanged meal is 4 mg.
in the urine
1.5 hr Onset, 20 min; F = 73%; metabolized to Skip dose if meal is
peak, 1 hr;
inactive products
skipped.
duration, 2–4 (predominantly) that
hr
are excreted in the urine
(83%) and feces (10%)

8. Second generation sulfonylurea
Drug
Typical dosing
Glimepiride 1–2 mg/QD
(Amaryl) 1, 2, initially; usual
4 mg
maintenance
dose is 1–4 mg.
Min and Max
daily dose
1–8 mg QD
Mean Duration
t1/2 of Activity
9 hr
24 hr
Bioavailability ,
Metabolism, and
Excretion
F = 100% completely
metabolized by liver.
Principal metabolite is
slightly active (30% of
parent compound).
Excreted by the urine
(60%) and feces (40%)
Comments
Probably safe in patients with
renal failure, but low initial
doses recommended for older
patients and those with renal
insufficiency. Incidence of
hypoglycemia may be lower
than other long-acting
sulfonylureas

9. Second generation sulfonylurea
Drug
Typical dosing
Min and Max
daily dose
Mean Duration
t1/2 of Activity
Glipizide
2.5 mg/QD in
2.5–40 mg QD 2–4 hr
(Glucotrol) 5, elderly, 5 mg QD
or BIDa
10 mg
in others; ↑ by
2.5 or 5 mg every
1–2 weeks.
Glipizide
5 mg/QD; ↑ by 5 5–20 mg QD 4–13 hr
extended–
mg every 1–2
release
weeks.
(Glucotrol XL)
5 mg
Bioavailability ,
Metabolism, and
Excretion
12–24 hr Metabolized to
inactive compounds
24 hr
Comments
No special precautions daily
dose >15 mg should be divided.
Dose 30 min before meals
Use with caution in patients
with preexisting GI narrowing
owing to possible obstruction

10. Second generation sulfonylurea
Drug
Typical dosing
Min and Max
daily dose
Mean Duration
t1/2 of Activity
Bioavailability ,
Metabolism, and
Excretion
Comments
Glyburide
1.25 mg/QD in 1.25–20 mg QD 4–13 hr 12–24 hr
(Diabeta,
elderly, 2.5 mg
or BID
Micronase) QD in others; ↑
1.25, 2.5, 5 mgby 1.25 or 2.5 mg
every 1–2 weeks.
Metabolized to
inactive/weakly
inactive compounds;
50% excreted in urine
and 50% in feces
Caution in elderly patients with
renal failure and others
predisposed to hypoglycemia.
Daily doses >10 mg should be
divided
Micronized 1.5 mg/QD; ↑ by 1.0–12 mg QD
Glyburide
1.5 mg every 1–2
(Glynase
weeks.
presTab) 1.5, 3
mg
Metabolized to
inactive/weakly
inactive compounds;
50% excreted in urine
and 50% in feces
Daily doses >6 mg should be
divided. ↑ bioavailability
relative to original formulation.
Resulted in reduced dose
4 hr
24 hr

11. Incretin based therapy
Drug
Typical dosing
Min and Mean Duration
Max daily t1/2 of Activity
dose
Bioavailability ,
Metabolism, and
Excretion
Comments
GLP-1 receptor agonists/incretin mimetics
Exenatide
(Byetta)
5 mcg SC BID; ↑ to
5–10 2.4 hr Cmax is at Glomerular
10 mcg SC BID after mcg BID
2.1 hr; filtration
1 month
duration
10 hr
Take within 60 min before
morning and evening meal.
Nausea usually subsides over
time
DPP-4 Inhibitors
Sitagliptin
(Januvia)
100 mg QD
CrCl ≥30 to <50
mL/min: 50 mg QD
CrCl <30 mL/min: 25
mg QD
100 mg
QD
12.4 hr
24 hr
F = 87%; ~79%
Requires dose adjustment in
excreted unchanged in renal insufficiency.
urine.

12. Second generation sulfonylurea
Drug
Pramlintide
(Symlin)
Typical dosing
Type 1 DM: 15
mcg SC before
major meals;
↑by 15-mcg
increments after
minimum of 3
days
Type 2 DM: 60
mcg SC before
major meals; ↑
to 120 mcg after
3–7 days
Min and Max
daily dose
Type 1: 15–60
mcg before
major meals
Type 2: 60 or
120 mcg
before major
meals
Mean
t1/2
Duration of
Activity
48 min Cmax is 20
minutes
Bioavailability ,
Metabolism, and
Excretion
F = 30%–40%;
metabolized by
kidneys
Comments
Reduce mealtime insulin dose
by 50%. Titrate dose if no
significant nausea.

13. Potential combinations of antihyperglycemic agents
Eat healthy, Weight Control, Increase Physical Activity
Metformin
Proceed to 2-drug combination if A1c goals are not reached
Metformin +
Sulfonylurea
(SU)
Thiazolidinedione DDP-4 Inhibitors GLP-1 receptor agonist Basal insulin
(TZD)
(DPP-4-I)
(GLP-1-RA)
Metformin +
Sulfonylurea
(SU)
+TZD
or DPP-4-I
or GLP-1-RA
Consider beginning at this stage in patients wih
very high A1C (eg, ≥9%).
Thiazolidinedione DDP-4 Inhibitors GLP-1 receptor agonist Basal insulin
(TZD)
(DPP-4-I)
(GLP-1-RA)
+SU
+SU
+SU
+TZD
or DPP-4-I
or TZD
or TZD
or DPP-4-I
or GLP-1-RA
or insulin
or insulin
or GLP-1-RA
Consider rapid-acting, nonsulfonylurea
secretagogues (meglitinides) in patients with
irregular meal schedules or who develop late
postprandial hypoglycemia on sulfonylureas
Certain noninsulin agents may be continued
with insulin

14. A case approach to type-2 diabetes
L.H. is a 45-year-old, moderately overweight, Mexican-American (height, 5 feet 5 inches;
weight, 160 lbs; BMI 26.6 kg/m2). She was treated for recurrent monilial infections, when
noted glucosuria on routine urinalysis.
On 2 separate occasions: her FPG was 150 mg/dL and 167 mg/dL.
L.H. denies any symptoms of polyphagia or polyuria, although lately she has
been more thirsty than usual. She does complain of lethargy and often takes
afternoon naps.
Other medical problems include HTN, which is well controlled on lisinopril 20
mg/day, and recurrent monilial infections, which are treated with
fluconazole.
She has given birth to four children (birth weights, 7, 8.5, 10, and 11 lb) and
was told during her last pregnancy that she had “borderline diabetes.”

15. A case approach to type-2 diabetes
She currently works as a loan officer in a local bank and spends her weekends “catching up
on her sleep” and reading. L.H. has been smoking one pack of cigarettes per day for 20
years and drinks an occasional glass of wine
She drinks at least two regular sodas daily and has “large” glass of orange juice
every morning. Her family history is significant for a sister, aunt, and grandmother
with type 2 diabetes; all have “weight problems.”
L.H.'s mother is alive and well at age 77; her father died of a heart attack at
age 47.
Laboratory assessment reveals an FPG of 147 mg/dL (normal, 70–
100); fasting plasma triglycerides of 400 mg/dL (normal, <150 mg/dL);
and an HbA1c of 9.2% (normal, 4%–6%). All other values (including the
complete blood count, electrolytes, LFTs, and renal function tests) are
within normal limits. L.H. is given the diagnosis of type 2 diabetes.

16. What features in L.H.'s history and physical examination are
consistent with this diagnosis?
FPG concentration of 126 mg/dL or higher on more than one occasion
An elevated HbA1c,
High BMI with central obesity
Age greater than 40
Family history of diabetes
Mexican American descent.
Delivering large babies, (undiagnosed gestational diabetes)
Mild signs and symptoms of hyperglycemia (including
increased thirst and lethargy), recurrent monilial infections,
hypertriglyceridemia, and indications of CVD (hypertension)
also are typical in patients with type 2 diabetes

17. What should the goals of therapy be for L.H. ?
Which biochemical indices should be monitored?
Eliminating acute symptoms of hyperglycemia
Avoiding hypoglycemia
Reducing cardiovascular risk factors
Preventing or slowing the progression of both microvascular and
macrovascular diabetic complications.
Biochemical indices that should be followed to monitor
L.H.'s response to therapy include fasting, postprandial, and
preprandial blood glucose concentrations, HbA1c values,
fasting triglyceride levels, as well as LDL and HDL cholesterol
concentrations. Initial metabolic goals for L.H. should be an
HbA1c value of <7%, an FPG of <130 mg/dL, postprandial
glucose concentrations below 180 mg/dL, LDL-cholesterol
below 100 mg/dL, and triglycerides below 150 mg/dL.

18. How should L.H. be managed initially?
Lifestyle changes that will minimize insulin resistance and risk for CVD.
Overweight (BMI 25.0–29.9) or obese (BMI ≥30.0) type 2 individuals
need to be on lower calorie, low-fat, low-cholesterol diet.
Regular exercise
Smoking cessation
Aggressive management of dyslipidemia and hypertension.
When signs and symptoms are mild, diet and
exercise alone can correct glucose intolerance.
SMBG monitoring and patient education.

19. Diabetes type-2 initial treatment
Metformin is favored as a first-choice agent for overweight, type 2
diabetics as long as there are no contraindications to its use.
This is because metformin lowers blood
glucose by decreasing hepatic glucose output
and insulin resistance (indirectly) without
causing weight gain or hypoglycemia.
Metformin also has beneficial effects on
plasma lipid concentrations as well.
A drawback to metformin is that it requires
multiple daily dosing and its dose also
must be titrated to minimize GI effects.
After the dose is established, it is possible
to use a long-acting product that can be
dosed once daily.
Further adjustments and
more drugs
Basal insulin SU, TZD
Lifestyle + Metformin
Renal function tests should be evaluated before the drug is initiated.

20. L.H. is started on metformin 500 mg BID with food and instructed to
increase her dosage to 500 mg Q AM and 1,000 mg Q PM after 1 week.
Three days after starting metformin, she phones the clinic complaining of
nausea and diarrhea. She admits to taking her doses on an empty stomach.
How should L.H.'s symptoms be addressed?
GI disturbances such as diarrhea, bloating, anorexia, abdominal
discomfort, nausea, and metallic taste often dissipate with time
and can be minimized by initiating metformin in a single, 500- or
850-mg dose at breakfast or with the patient's largest meal of the
day.
Consistently taking metformin with food significantly
minimizes the GI side effects. The dosage should be slowly
increased (e.g., 500 mg/day every 2 weeks) until the
appropriate clinical effect is achieved or the patient is taking
the maximum dose (1,000 mg twice daily or 850 mg three
times a day).

21. How should metformin therapy be monitored in L.H.?
L.H. should be encouraged to perform SMBG.
Have an HbA1c test performed quarterly until goals achieved.
Additional evidence may include an improved lipid profile and some weight loss.
Initially, it is important to follow GI problems
L.H. should be warned to bring to the attention of her
physician any sudden symptoms of shortness of breath,
weakness, and malaise (Lactic Acidosis).
A baseline SrCr, LFTs, and complete blood count should
be obtained .
Lifestyle changes that will minimize insulin resistance
and risk for CVD.

22. What are the advantages and disadvantages of SMBG tests? When and how often
should L.H. be instructed to test her blood glucose concentrations?
We often recommend SMBG for motivated type 2 patients who are learning to adjust their
carbohydrate intake and portion sizes and want to measure how well medications and
lifestyle changes are working to improve their glucose control.
Initially, we may suggest testing four times daily before meals
and at bedtime for 1 week so that the patient can observe his
or her glucose profiles. Later, once the desired HbA1c has been
achieved, we recommend a minimum of testing blood glucose
twice daily, but at various times to evaluate fasting glucose
concentrations

23. Treatment algorithm for type-2 diabetes
Diagnosis
Lifestyle modifications
+ Metformin
Yes
Add basal insulin
Most effective
HbA1c≥7
Add sulfonylurea
Least expensive
HbA1c≥7
No
yes
Intensify
insulin
Add glitazone
No hypoglycemia
HbA1c≥7
yes
Add
glitazone
Add Insulin
HbA1c≥7
yes
Intensive insulin + metformin ± glitazone
HbA1c≥7
yes
Add
Sulfonylurea
yes

24. Treating diabetes under special circumstances
Circumstance
Avoid
Consider
Patients with decreased renal Acarbose
function
Long-acting SFUs
(e.g., glyburide)
Metformin
Glipizide
Glimepiride
Insulin
Glinides (Repaglinide/ nateglinide)
Sitagliptin
Thiazolidinediones
Patients with impaired liver
function
Acarbose
Metformin
Thiazolidinediones
? SFUs
(severe liver dysfunction)
Insulin
Repaglinide
Exenatide
Sitagliptin
Miglitol
Patients who are obese or
gaining excessive weight
Insulin
Sulfonylureas
Repaglinide
? Thiazolidinediones
Acarbose
Miglitol
Metformin

25. Treating diabetes under special circumstances
Circumstance
Avoid
Consider
Patients with preexisting
edema
Thiazolidinediones
SFUs
Glinides
Exenatide
Sitagliptin
Patients with heart failure
Thiazolidinediones
Metformin
SFUs
Glinides
Exenatide
Sitagliptin
Insulin
Patients experiencing
Insulin
hypoglycemia due to irregular Long-acting SFUs
eating patterns
Acarbose
Metformin
Repaglinide/nateglinide
Thiazolidinediones
Exenatide
Sitaglipin

26. Pharmacottherapy
Anas Bahnassi PhD CDM CDE
abahnassi@gmail.com
http://www.twitter.com/abpharm
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