Week

Diabetes Mellitus
2
Part 2
Anas Bahnassi PhD CDM CDE
Oral hypoglycemic agents sites of action

PANCREAS
LIVER MUSCLE ADIPOSE TISSUE

INSULIN Secretion
Sulfonylureas
Meglitinides
GLUCOSE PRODUCTION PERIPHERAL
Insulin
Biguanides GLUCOSE UPTAKE
Amylin
Thiazolidinediones Thiazolidinediones
(Biguanides)
INTESTINE

GLUCOSE ABSORPTION
α- glucosidase inhibitors
INTESTINAL HORMONES
Incretin
 α-Glucosidase inhibitors

Drug Typical dosing Min and Max Mean Duration of Bioavailability ,

daily dose t1/2 Activity Metabolism, and Comments
Excretion

Acarbose 25–100 mg with first biteMinimum: 25 2.8 hr Affects absorption F = 0.5%–1.7%; Titrate doses
(Precose) 25, of each meal. mg TID; of complex extensively metabolized slowly to avoid
50, 100 mg Begin with 25 mg; ↑ by Maximum carbohydrates in a by GI amylases to GI effects
25 mg/meal every 4–8 dose is 50 mg single meal inactive products; 50%
weeks. TID if ≤60 kg; excreted unchanged in
100 mg TID if the feces
>60 kg.
Miglitol 25–100 mg with first bite Minimum: 25 2 hr Affects absorption Dose of 25 mg is
(Glyset) 25, of each meal. mg TID of complex completely absorbed;
50, 100 mg Begin with 25 mg; ↑ by Maximum: 100 carbohydrates in a dose of 100 mg 50–70%
25 mg/meal every 4–8 mg TID single meal absorbed; elimination by
weeks. renal excretion as
unchanged drug
 Biguanides

Drug Typical dosing Min and Max Mean t1/2 Duration of Bioavailability ,
daily dose Activity Metabolism, and Comments
Excretion

Metformin Begin with 500 mg 0.5–2.5 g BID Plasma, 6.2 hr 6–12 hr F = 50%–60%; Take with food. Avoid
(Glucophage) 500, QD or /BID; ↑ by or TID Whole blood, excreted in patients with renal
850, 1000 mg; 500 500 mg QD every 17.6 hr unchanged in dysfunction or those
mg/mL liquid 1–2 weeks. urine who could be
predisposed to lactic
acidosis (e.g.,
Metformin 500–1,000 mg/QD 1,500–2,000 Active drug is 24 hr alcoholism, CHF, severe
extended-release with evening mg QD released respiratory disorders,
(Glucophage XR) meal; ↑ by 500 slowly liver failure)
500, 750, 1000 mg mg every 1–2
weeks.
 Nonsulfonylurea Insulin Secretagogues (Glinides)

Drug Typical dosing Min and Max Mean Duration of Bioavailability ,

daily dose t1/2 Activity Metabolism, and Comments
Excretion

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

Drug Typical dosing Min and Mean t1/2 Duration of Bioavailability ,

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

Drug Typical dosing Min and Max Mean Duration of Bioavailability ,

daily dose t1/2 Activity Metabolism, and Comments
Excretion

Repaglinide If HbA1c is <8% or if this is 0.5–4 mg with 1 hr Cmax is at 1 hr; F = 56%; 92% Take only with
(Prandin) 0.5, first drug, begin with 0.5 each meal (16 duration is metabolized to inactive meals. Skip dose if
1, 2 mg mg with each meal. For mg/day)/TID– approximately products by the liver; meal is skipped.
others, begin with 1–2 QID 2–3 hr 8% excreted as Maximum dose per
mg/meal. metabolites unchanged meal is 4 mg.
in the urine
Nateglinide 120 mg TID 1–30 min 60 or 120 mg 1.5 hr Onset, 20 min; F = 73%; metabolized to Skip dose if meal is
(Starlix) 60, before meals; 60 mg TID for TID peak, 1 hr; inactive products skipped.
120 mg patients with near-normal duration, 2–4 (predominantly) that
HbA1c at initiation. hr are excreted in the urine
(83%) and feces (10%)
 Second generation sulfonylurea

Drug Typical dosing Min and Max Mean Duration Bioavailability ,

daily dose t1/2 of Activity Metabolism, and Comments
Excretion

Glimepiride 1–2 mg/QD 1–8 mg QD 9 hr 24 hr F = 100% completely
(Amaryl) 1, 2, initially; usual metabolized by liver.
4 mg maintenance Principal metabolite is
dose is 1–4 mg. slightly active (30% of
parent compound).
Excreted by the urine
(60%) and feces (40%)
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
 Second generation sulfonylurea

Drug Typical dosing Min and Max Mean Duration Bioavailability ,

daily dose t1/2 of Activity Metabolism, and Comments
Excretion

Glipizide 2.5 mg/QD in 2.5–40 mg QD 2–4 hr 12–24 hr Metabolized to No special precautions daily
(Glucotrol) 5, elderly, 5 mg QD or BIDa inactive compounds dose >15 mg should be divided.
10 mg in others; ↑ by Dose 30 min before meals
2.5 or 5 mg every
1–2 weeks.

Glipizide 5 mg/QD; ↑ by 5 5–20 mg QD 4–13 hr 24 hr Use with caution in patients

extended– mg every 1–2 with preexisting GI narrowing
release weeks. owing to possible obstruction
(Glucotrol XL)
5 mg
 Second generation sulfonylurea

Drug Typical dosing Min and Max Mean Duration Bioavailability ,

daily dose t1/2 of Activity Metabolism, and Comments
Excretion

Glyburide 1.25 mg/QD in 1.25–20 mg QD 4–13 hr 12–24 hr Metabolized to Caution in elderly patients with
(Diabeta, elderly, 2.5 mg or BID inactive/weakly renal failure and others
Micronase) QD in others; ↑ inactive compounds; predisposed to hypoglycemia.
1.25, 2.5, 5 mgby 1.25 or 2.5 mg 50% excreted in urine Daily doses >10 mg should be
every 1–2 weeks. and 50% in feces divided

Micronized 1.5 mg/QD; ↑ by 1.0–12 mg QD 4 hr 24 hr Metabolized to Daily doses >6 mg should be

Glyburide 1.5 mg every 1–2 inactive/weakly divided. ↑ bioavailability
(Glynase weeks. inactive compounds; relative to original formulation.
presTab) 1.5, 3 50% excreted in urine Resulted in reduced dose
mg and 50% in feces
 Incretin based therapy

Drug Typical dosing Min and Mean Duration Bioavailability ,

Max daily t1/2 of Activity Metabolism, and Comments
dose Excretion

GLP-1 receptor agonists/incretin mimetics

Exenatide 5 mcg SC BID; ↑ to 5–10 2.4 hr Cmax is at Glomerular Take within 60 min before
(Byetta) 10 mcg SC BID after mcg BID 2.1 hr; filtration morning and evening meal.
1 month duration Nausea usually subsides over
10 hr time
DPP-4 Inhibitors
Sitagliptin 100 mg QD 100 mg 12.4 hr 24 hr F = 87%; ~79% Requires dose adjustment in
(Januvia) CrCl ≥30 to <50 QD excreted unchanged in renal insufficiency.
mL/min: 50 mg QD urine.
CrCl <30 mL/min: 25
mg QD
 Second generation sulfonylurea

Drug Typical dosing Min and Max Mean Duration of Bioavailability ,

daily dose t1/2 Activity Metabolism, and Comments
Excretion

Pramlintide Type 1 DM: 15 Type 1: 15–60 48 min Cmax is 20 F = 30%–40%; Reduce mealtime insulin dose
(Symlin) mcg SC before mcg before minutes metabolized by by 50%. Titrate dose if no
major meals; major meals kidneys significant nausea.
↑by 15-mcg Type 2: 60 or
increments after 120 mcg
minimum of 3 before major
days meals
Type 2 DM: 60
mcg SC before
major meals; ↑
to 120 mcg after
3–7 days
Potential combinations of antihyperglycemic agents

Eat healthy, Weight Control, Increase Physical Activity

Metformin
Proceed to 2-drug combination if A1c goals are not reached
Consider beginning at this stage in patients wih
Metformin + very high A1C (eg, ≥9%).

Sulfonylurea Thiazolidinedione DDP-4 Inhibitors GLP-1 receptor agonist Basal insulin

(SU) (TZD) (DPP-4-I) (GLP-1-RA)

Metformin + Consider rapid-acting, nonsulfonylurea

secretagogues (meglitinides) in patients with
irregular meal schedules or who develop late
Sulfonylurea Thiazolidinedione DDP-4 Inhibitors GLP-1 receptor agonist Basal insulin
postprandial hypoglycemia on sulfonylureas
(SU) (TZD) (DPP-4-I) (GLP-1-RA)
+TZD +SU +SU +SU +TZD
or DPP-4-I or DPP-4-I or TZD or TZD or DPP-4-I
or GLP-1-RA or GLP-1-RA or insulin or insulin or GLP-1-RA Certain noninsulin agents may be continued
with insulin
 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.”
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.
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
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.
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.
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 Further adjustments and
plasma lipid concentrations as well. more drugs
A drawback to metformin is that it requires
multiple daily dosing and its dose also Basal insulin SU, TZD
must be titrated to minimize GI effects.
After the dose is established, it is possible
to use a long-acting product that can be Lifestyle + Metformin
dosed once daily.
Renal function tests should be evaluated before the drug is initiated.
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).
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.
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
Treatment algorithm for type-2 diabetes

Diagnosis
Yes
Lifestyle modifications
+ Metformin
Add basal insulin Add sulfonylurea Add glitazone
HbA1c≥7 Most effective Least expensive No hypoglycemia

HbA1c≥7 HbA1c≥7 HbA1c≥7

No yes yes yes yes

Intensify Add Add

Add Insulin
insulin glitazone Sulfonylurea

HbA1c≥7

yes

Intensive insulin + metformin ± glitazone

Treating diabetes under special circumstances

Circumstance Avoid Consider

Patients with decreased renal Acarbose Glipizide
function Long-acting SFUs Glimepiride
(e.g., glyburide) Insulin
Metformin Glinides (Repaglinide/ nateglinide)
Sitagliptin
Thiazolidinediones
Patients with impaired liver Acarbose Insulin
function Metformin Repaglinide
Thiazolidinediones Exenatide
? SFUs Sitagliptin
(severe liver dysfunction) Miglitol

Patients who are obese or Insulin Acarbose

gaining excessive weight Sulfonylureas Miglitol
Repaglinide Metformin
? Thiazolidinediones
Treating diabetes under special circumstances

Circumstance Avoid Consider

Patients with preexisting Thiazolidinediones SFUs

edema Glinides
Exenatide
Sitagliptin

Patients with heart failure Thiazolidinediones SFUs

Metformin Glinides
Exenatide
Sitagliptin
Insulin
Patients experiencing Insulin Acarbose
hypoglycemia due to irregular Long-acting SFUs Metformin
eating patterns Repaglinide/nateglinide
Thiazolidinediones
Exenatide
Sitaglipin
 Pharmacottherapy
Anas Bahnassi PhD CDM CDE
abahnassi@gmail.com

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