07 Endocrine
07 Endocrine
07 Endocrine
Endocrine and
Metabolic Disorders
Brian K. Irons, Pharm.D., FCCP,
BCACP, BCPS, BC-ADM
Texas Tech University Health Sciences
Center School of Pharmacy
Lubbock, Texas
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7. A 76-year-old woman recently given a diagnosis of the past 2 years. His A1c today is 7.8%. His fasting
Hashimoto’s disease presents with mild symptoms morning BG readings are consistently at goal. His
of lethargy, weight gain, and intolerance to cold. after meal glucose readings average 190–200 mg/
Her TSH is above and her free T4 is below nor- dL. Which one of the following options would be
mal limits. She has a history of hypertension and most appropriate for this patient?
coronary artery bypass surgery 2 years ago. Which A. Increase metformin to 1000 mg 3 times/day.
one of the following would be the most appropriate B. Add insulin glargine 10 units once daily.
initial treatment for this patient? C. Switch from metformin to insulin glargine 10
A. Levothyroxine 25 mcg once daily. units once daily.
B. Levothyroxine 50 mcg once daily. D. Add saxagliptin 5 mg once daily.
C. Liothyronine 25 mcg once daily.
D. Liothyronine 50 mcg once daily. 11. A 34-year-old woman has a BMI of 33 kg/m 2. With
dietary changes, she has lost 2 lb in 6 months. She
8. A woman with type 2 DM has an A1c of 8.6%. She exercises regularly but is unable to do more be-
is receiving insulin glargine (60 units once daily at cause she has two jobs and young children. She has
bedtime) and insulin aspart (8 units before break- a history significant for substance abuse. Which
fast, 7 units before lunch, and 12 units before din- one of the following would be the best recommen-
ner). She is very consistent in her carbohydrate dation to help her lose weight?
intake at each meal. Her morning fasting plasma A. Continue her diet and exercise routine;
glucose (FPG) and premeal blood glucose (BG) additional intervention is unwarranted.
readings have consistently averaged 112 mg/dL. B. Initiate diethylpropion 25 mg 3 times/day
Her bedtime readings are averaging between 185 with meals.
and 200 mg/dL. Which one of the following is the C. Initiate phentermine 15 mg 3 times/day
best insulin adjustment to improve her overall gly- before meals.
cemic control? D. Initiate orlistat 120 mg 3 times/day with meals.
A. Increase her breakfast aspart to 10 units.
B. Increase her dinnertime aspart to 14 units. 12. A 53-year-old Hispanic woman has a BMI of 44
C. Increase her bedtime glargine to 65 units. kg/m 2 and a history of gestational diabetes. Her
D. Increase her bedtime glargine to 70 units. mother and sister both have type 2 DM. She had
an A1c of 7.4% last month. Her fasting glucose con-
9. A 53-year-old woman with a history of Graves centration today is 178 mg/dL. Which one of the
disease underwent ablative therapy 3 years ago. following is the best course of action?
She experienced significant symptom relief and A. Diagnose type 2 DM and begin treatment.
became euthyroid. Her thyroid laboratory values B. Diagnose type 1 DM and begin treatment.
today include TSH 0.12 mIU/L (normal 0.5–4.5 C. Obtain another A1c today.
mIU/L) and a free T4 concentration of 3.8 g/dL D. Obtain another glucose concentration another
(normal 0.8–1.9 ng/dL). She states that many of day.
her previous symptoms have now returned but are
mild. Which of the following would be the most
13. A 66-year-old man has a history of type 2 DM. His
appropriate treatment option for her condition?
current therapy includes metformin 1000 mg twice
A. Methimazole. daily, glyburide 10 mg twice daily, aspirin 81 mg
B. Thyroidectomy. once daily, and lisinopril 20 mg once daily. Today,
C. PTU. his A1c is 6.9%, blood pressure is 126/78 mm Hg,
D. Metoprolol. and fasting lipid panel is as follows: total cholester-
ol 212 mg/dL, low-density lipoprotein cholesterol
10. A 65-year-old man with type 2 DM for 6 years has (LDL-C) 118 mg/dL, high-density lipoprotein cho-
been receiving metformin 1000 mg twice daily for lesterol (HDL-C) 45 mg/dL, and triglycerides (TG)
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I. THYROID DISORDERS
Hypothalamus
TRH - ve
Pituitary
TSH
- ve
Thyroid
T3 T4
Figure 1. Hypothalamus-pituitary-thyroid axis.a
a
T4 is converted to T3 by peripheral tissue. Only unbound (free) thyroid
hormone is biologically active.
T3 = triiodothyronine; T4 = thyroxine; TRH = thyrotropin-releasing hormone;
TSH = thyroid-stimulating hormone; - ve = negative feedback loop.
A. Classification
1. Hyperthyroid disorders (thyrotoxicosis)
a. Toxic diffuse goiter (Graves disease): Most common hyperthyroid disorder
i. Autoimmune disorder
ii. Thyroid-stimulating antibodies directed at thyrotropin receptors mimic thyroid-stimulating
hormone (TSH) and stimulate triiodothyronine/thyroxine (T3/T4) production.
b. Pituitary adenomas: Produce excessive TSH secretion that does not respond to normal T3 feedback
c. Toxic adenoma: Nodule in thyroid, autonomous of pituitary and TSH
d. Toxic multinodular goiter (Plummer’s disease): Several autonomous follicles that, if large enough,
cause excessive thyroid hormone secretion
e. Painful subacute thyroiditis: Self-limiting inflammation of the thyroid gland caused by viral
invasion of the parenchyma, resulting in release of stored hormone
f. Drug induced (e.g., excessive exogenous thyroid hormone doses, amiodarone therapy)
2. Hypothyroid disorders
a. Hashimoto’s disease: Most common hypothyroid disorder
i. Autoimmune-induced thyroid injury resulting in decreased thyroid secretion
ii. Disproportionately affects women
b. Iatrogenic: Thyroid resection or radioiodine ablative therapy for treatment of hyperthyroidism
c. Iodine deficiency or excessive intake
d. Secondary causes
i. Pituitary insufficiency (failure to produce adequate TSH secretion)
ii. Drug induced (e.g., amiodarone, lithium)
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B. Diagnosis
1. Hyperthyroid disorders
a. Elevated total T4 and free T4 serum concentrations
b. Suppressed TSH concentrations (except in TSH-secreting adenomas)
c. If examination and history do not provide the exact etiology, radioactive iodine uptake may be
employed.
i. Radioactive iodine uptake elevated if thyroid gland is actively and excessively secreting T4
and/or T3: Graves disease, TSH-secreting adenoma, toxic adenoma, multinodular goiter
ii. Radioactive iodine uptake is suppressed in disorders caused by thyroiditis or hormone ingestion.
d. Can also assess for the presence of various thyroid-related antibodies (thyroid stimulating,
thyrotropin receptor or thyroperoxidase), thyroglobulin, and thyroid biopsy
2. Hypothyroid disorders
a. Decreased total T4 and free T4 serum concentrations
b. Elevated TSH concentrations (normal or low if secondary hypothyroidism is the etiology)
c. Thyroid antibodies: Antithyroid peroxidase and antithyroglobulin autoantibodies
C. Clinical Presentation
1. Hyperthyroid disorders
a. Weight loss/increased appetite
b. Lid lag
c. Heat intolerance
d. Goiter
e. Fine hair
f. Heart palpitations/tachycardia
g. Nervousness, anxiety, insomnia
h. Menstrual disturbances (lighter or more infrequent menstruation, amenorrhea) caused by
hypermetabolism of estrogen
i. Sweating or warm, moist skin
j. Exophthalmos, pretibial myxedema in Graves disease
2. Hypothyroid disorders
a. Cold intolerance
b. Dry skin
c. Fatigue, lethargy, weakness
d. Weight gain
e. Bradycardia
f. Slow reflexes
g. Coarse skin and hair
h. Periorbital swelling
i. Menstrual disturbances (more frequent or longer menstruation, painful menstruation,
menorrhagia) caused by hypometabolism of estrogen
j. Goiter (primary hypothyroidism)
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Patient Case
1. A 63-year-old woman has Hashimoto’s disease. Her thyroid laboratory values today include the following:
TSH 5.6 mIU/L (normal 0.5–4.5 mIU/L) and a free T4 concentration of 0.5 ng/dL (normal 0.8–1.9 ng/dL).
She feels consistently rundown and has dry skin not responding to use of hand creams. Which one of the
following would be considered the best drug for initial treatment of her condition?
A. Levothyroxine.
B. Liothyronine.
C. Desiccated thyroid.
D. Methimazole.
2. A 43-year-old woman has received a diagnosis of Graves disease. She is reluctant to try ablative therapy and
wishes to undergo oral pharmacotherapy first. Her thyroid laboratory values today include TSH 0.22 mIU/L
(normal 0.5–4.5 mIU/L) and a free T4 concentration of 3.2 ng/dL (normal 0.8–1.9 ng/dL). She is anxious and
always feels warm when others complain it is too cold. Which one of the following would be considered the
best drug for initial treatment of her condition?
A. Lugol’s solution.
B. Propylthiouracil.
C. Atenolol.
D. Methimazole.
3. A 66-year-old white woman has a TSH concentration of 10.8 (normal 0.5–4.5 mIU/L) and a free T4 concen-
tration of 1.0 (normal 0.8–1.9 ng/dL). She has dry skin and feels lethargic. Which one of the following is the
most correct assessment?
A. She has subclinical hypothyroidism, which should be treated.
B. She has subclinical hyperthyroidism, which should be treated.
C. She has subclinical hypothyroidism, which should not be treated.
D. She has subclinical hyperthyroidism, which should not be treated.
E. Pharmacotherapy
1. Hyperthyroidism
a. Ablative therapy: Treatment of choice for Graves disease, toxic nodule, multinodular goiter:
Radioactive iodine ablative therapy and surgical resection for adenomas based on patient
preferences or comorbidities. Ablative therapy often results in hypothyroidism.
b. Antithyroid pharmacotherapy usually reserved for:
i. Awaiting ablative therapy or surgical resection
(a) Depletes stored hormone
(b) Minimizes risk of posttreatment hyperthyroidism because of thyroiditis
ii. Not an ablative or surgical candidate (e.g., serious cardiovascular disease, candidate not likely
to be adherent to radiation safety)
iii. When ablative therapy or surgical resection fails to normalize thyroid function
iv. High probability of remission with oral therapy with Graves disease
(a) Mild disease
(b) Small goiter
(c) Low or negative antibody titers
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(a) Primarily used for symptomatic relief (e.g., palpitations, tachycardia, tremor, anxiety)
(b) Guidelines recommend use in elderly, symptomatic patients, and others with heart rates
greater than 90 beats/minute. Consider in all symptomatic patients.
(c) Poor remission rates: 20%–35%
(d) Primary role is treatment of thyroiditis, which is usually self-limiting, and for acute
management of symptoms during thyroid storm (see below).
(e) Alternatives to β-blockers: Clonidine, nondihydropyridine calcium channel blocker
e. Iodines (e.g., Lugol’s solution, saturated solution of potassium iodide)
i. Mechanism of action: Inhibits the release of stored thyroid hormone. Minimal effect on
hormone synthesis. Helps decrease vascularity and size of gland before surgery
ii. Dosing
(a) Lugol’s solution (6.3–8 mg of iodide per drop)
(b) Saturated solution of potassium iodide (38–50 mg of iodide per drop)
(c) Usual daily dose: 120–400 mg mixed with juice or water, split 3 times/day
iii. Adverse effects
(a) Hypersensitivity
(b) Metallic taste
(c) Soreness or burning in mouth or tongue
(d) Do not use in the days before ablative surgery (may reduce uptake of radioactive iodine).
iv. Efficacy
(a) Limited efficacy after 7–14 days of therapy because thyroid hormones release will resume
(b) Primary use is temporary before surgery (7–10 days) to shrink the size of the gland.
(c) Used postablative therapy (3–7 days) to inhibit thyroiditis-mediated release of stored
hormone
(d) Used acutely in thyroid storm
2. Hypothyroidism
a. Levothyroxine (drug of choice)
i. Mechanism of action: Synthetic T4
ii. Dosing
(a) Initial: 50–75 mcg by mouth once daily (25 mcg once daily in the elderly or in those with
existing cardiovascular disease)
(b) Dose titration based on response (control of symptoms, normalization of TSH and free T4)
(c) Usually dosed in the morning on empty stomach, separate from other medications
(d) Average maintenance dose about 1.6–1.7 mcg/kg/day or 125 mcg. (Elderly may require
slower titration and lower total daily doses.)
(e) Daily requirements will be higher in pregnancy.
iii. Monitoring
(a) Six weeks is appropriate to assess patient response (about a 7-day half-life for T4). May
take longer for TSH to achieve steady-state concentrations
(b) Use free T4 rather than TSH if secondary hypothyroidism
(c) As titrated to erythroid, some concurrent drug therapy may need to be adjusted (e.g.,
warfarin, phenytoin, insulin, sedatives).
iv. Adverse effects
(a) Hyperthyroidism
(b) Cardiac abnormalities (tachyarrhythmias, angina, myocardial infarction)
(c) Linked to risk of fractures (usually at higher doses or oversupplementation)
v. Efficacy: If levothyroxine is properly dosed, most patients will maintain TSH and free T4 in
the normal ranges and experience symptomatic relief.
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vi. Considered drug of choice secondary to its adverse effect profile, cost, lack of antigenicity,
and uniform potency
vii. Bioequivalency
(a) AACE recommends brand name levothyroxine (none of the other thyroid preparations
below are supported by AACE).
(b) Although legal, most clinicians recommend against changing from brand to generic and
vice versa. Staying with one product throughout therapy is recommended.
(c) TSH concentrations in bioequivalence testing were never performed; small changes in T4
between products may result in significant changes in TSH. Pharmacokinetic studies were
in normal subjects with normal thyroid function.
b. Liothyronine
i. Mechanism of action: Synthetic T3
ii. Dosing
(a) Initial: 25 mcg/day
(b) Average maintenance dose: 25–75 mcg/day
iii. Adverse effects: May have higher incidence of cardiac adverse effects than levothyroxine
because of faster onset of action (i.e., rapid absorption of liothyronine in the intestines,
leading to possible thyroid toxicity)
iv. Efficacy: If properly dosed, efficacy should be similar to levothyroxine. Has shorter half-life
than levothyroxine (1.5 vs. 7 days)
c. Liotrix
i. Mechanism of action: Synthetic T4/T3 in 4:1 ratio that “mimics” body’s natural ratio
ii. Seldom used. No real need because T4 is easily converted to T3
d. Desiccated thyroid (Thyroid USP)
i. Mechanism of action: Hog-, beef-, or sheep-derived levothyroxine, liothyronine in specific
ratios to thyroglobulin
ii. Not routinely recommended secondary to potential risk of hypersensitivity reactions
iii. Dosed in grains: One grain of Armour Thyroid equals about 100 mcg of levothyroxine.
Caution in calculation of “equivalent” doses
F. Subclinical Hypothyroidism
1. Definition: Elevated TSH (above upper limit of reference range) with normal T4. Often the result of
early Hashimoto’s disease
2. Risk?
a. TSH greater than 7.0 mIU/L in the elderly associated with increased risk of heart failure
b. TSH greater than 10 mIU/L associated with increased risk of coronary heart disease
3. Treatment of subclinical hypothyroidism is controversial because benefits in identified patients are
inconclusive.
4. Whom to treat
a. Patients with symptoms
b. TSH greater than 10 mIU/L
c. TSH between 5 and 10 mIU/L and goiter or antithyroid peroxidase antibodies present
5. If untreated, screen regularly for the development of overt hypothyroidism (decreased free T4
concentrations).
G. Subclinical Hyperthyroidism
1. Definition: Low (below lower limit of reference range) or undetectable TSH with normal T4
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2. Risk?
a. Associated with increased risk of atrial fibrillation in patients older than 60 years
b. Associated with increased risk of bone fracture in postmenopausal women
c. Conflicting data regarding mortality risk
3. Treatment (based on 2011 guidelines) similar to treating overt hyperthyroidism
a. Oral antithyroid drug-therapy alternative to ablative therapy in young patients with Graves disease
b. β-Blockers may be of benefit to control cardiovascular morbidity, especially with atrial fibrillation.
4. If untreated, screen regularly for the development of overt hyperthyroidism (increased free T4
concentrations).
H. Thyroid Storm
1. Severe and life-threatening decompensated thyrotoxicosis. Mortality rate may be as high as 20%.
2. Precipitating causes: Trauma, infection, antithyroid agent withdrawal, severe thyroiditis, postablative
therapy (especially if not adequate pretreatment)
3. Presentation: Fever, tachycardia, vomiting, dehydration, coma, tachypnea, delirium
4. Pharmacotherapy
a. Propylthiouracil
i. Dose 500- to 1000-mg loading dose; then 250 mg every 4 hours
ii. Blocks new hormone synthesis
b. Iodide therapy 1 hour after PTU initiation (dosed as above) to block hormone release
c. β-Blocker therapy: Esmolol commonly used (can use other agents [e.g., propranolol]) to control
symptoms and blocks conversion of T4 to T3
d. Acetaminophen as antipyretic therapy if needed (avoid NSAIDs [nonsteroidal anti-inflammatory
inhibitors] because of displacement of protein-bound thyroid hormones)
e. Corticosteroid therapy: Prednisone 25–100 mg/day in divided doses (or equivalent doses of
dexamethasone, hydrocortisone, etc.). Prophylaxis against relative adrenal insufficiency
I. Myxedema Coma
1. Severe and life-threatening decompensated hypothyroidism. Mortality rate 30%–60%
2. Precipitating causes: Trauma, infections, heart failure, medications (e.g., sedatives, narcotics,
anesthesia, lithium, amiodarone)
3. Presentation: Coma is not required and is uncommon despite terminology, altered mental state (very
common), diastolic hypertension, hypothermia, hypoventilation
4. Pharmacotherapy
a. Intravenous thyroid hormone replacement
i. T4: 100- to 500-mcg loading dose, followed by 75–100 mcg/day, until patient can tolerate oral
therapy. Lower the initial dose in frailer patients or in patients with established cardiovascular
disease.
ii. Some advocate the use of T3 over T4 given that T3 is more biologically active and T4/T3
conversion may be suppressed in myxedema coma. Cost and availability limit intravenous T3 use.
b. Antibiotic therapy: Given common infectious causes, some advocate empiric therapy with broad-
spectrum antibiotics.
c. Corticosteroid therapy
i. Hydrocortisone 100 mg every 8 hours (or equivalent steroid)
ii. Can be discontinued if random cortisol concentration not found to be depressed
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B. Diagnosis/Clinical Presentation
1. Acromegaly
a. Failure of an oral glucose tolerance test (OGTT) to suppress GH serum concentrations but with
elevated insulin-like growth factor-1 (IGF-1) (GH serum concentrations alone are not reliable
given the pulsatile pattern of release in the body.)
b. Clinical presentation (Note: Disease has a very slow onset, and many symptoms do not appear
for years.)
i. Excessive sweating
ii. Osteoarthritis, joint pain, paresthesias, or neuropathies
iii. Coarsening of facial features
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C. Therapy Goals
1. Acromegaly: Reduce GH and IGF-1 concentrations, decrease mortality, improve clinical symptoms.
Normal IGF-1 concentrations and suppressed GH concentrations post-OGTT
2. Hyperprolactinemia: Normalize prolactin concentrations, normal gonadotropin secretion, and symptom
relief
3. GH deficiency: Increased growth velocity, increased final adult height when treating children
Patient Case
4. A 28-year-old woman presents with acne, facial hair growth, and irregular menses that have lasted for 6–7
months. She has diagnoses of hypertension and depression. Her pituitary and thyroid tests have all come
back negative. Her current medications include atenolol and fluoxetine. Her prolactin level today was 112
ng/mL (normal 15–25 ng/mL). Which one of the following is the likely cause of her elevated prolactin level?
A. Atenolol.
B. Prolactin-secreting adenoma.
C. Pregnancy.
D. Fluoxetine.
D. Pharmacotherapy
1. Treatment of choice is surgical resection of tumor if causative.
2. Pharmacotherapy usually reserved for:
a. Control before surgery or irradiation
b. When surgery is not possible (usually requires lifelong pharmacotherapy)
c. Surgical failures or relapses after period of remission postsurgery
3. Acromegaly
a. Dopamine agonists (e.g., bromocriptine, cabergoline)
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5. GH deficiency
a. Recombinant GH (somatropin)
i. Dosing
(a) Depends on which of the various products are selected (dosed subcutaneously or
intramuscularly once daily)
(b) When to discontinue therapy on the basis of growth velocity is controversial.
(c) Once- or twice-monthly long-acting depot formulation is also available.
ii. Adverse effects
(a) Arthralgias, injection site pain
(b) Rare but serious cases of idiopathic intracranial hypertension have been reported.
iii. Efficacy: All products are considered equally efficacious.
b. Synthetic GH-releasing hormone (sermorelin)
i. Used in idiopathic GH deficiency
ii. Dosing: 0.03 mg/kg once daily subcutaneously
iii. Adverse effects: Minimal, injection site pain
iv. Efficacy: Improved growth velocity in children with positive provocative challenge (of little
use if not capable of secreting GH)
A. Classification
1. Hypersecretory cortisol diseases (a.k.a. Cushing’s syndrome)
a. ACTH-dependent: Result of excessive ACTH secretion (80% of cases)
i. Pituitary corticotroph adenoma (Cushing’s syndrome)
ii. Ectopic ACTH syndrome (extrapituitary tumor)
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Patient Case
5. A 44-year-old man has consistently high blood pressure (e.g., 172/98 mm Hg today), despite documented
adherence to two maximal-dose blood pressure medications. He has frequent headaches, increased thirst,
and fatigue. His urine-free cortisol is 45 mcg/24 hours (normal range 20–90), and his plasma aldosterone-
to-renin ratio is 125 (normal is less than 25). Which one of the following conditions is the most likely cause
of this patient’s uncontrolled hypertension?
A. Cushing’s syndrome.
B. Addison’s disease.
C. Hyperprolactinemia.
D. Hyperaldosteronism.
B. Diagnosis/Clinical Presentation
1. Cushing’s syndrome
a. Presence of hypercortisolism through 24-hour urine-free cortisol concentration
b. Differentiate etiology (key to treatment options)
i. Complex and beyond the scope of this chapter
ii. Plasma ACTH concentrations (normal or elevated in ACTH-dependent)
iii. Pituitary MRI (magnetic resonance imaging) (Cushing’s syndrome vs. ectopic ACTH syndrome)
iv. Overnight dexamethasone suppression test
c. Clinical presentation
i. Central obesity and facial rounding quite common
ii. Peripheral obesity and fat accumulation
iii. Myopathies
iv. Osteoporosis, back pain, compression facture
v. Abnormal glucose tolerance/diabetes
vi. Amenorrhea and hirsutism in women
vii. Lower abdominal pigmented striae (red to purple)
viii. Hypertension (principal cause of morbidity/mortality)
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2. Hyperaldosteronism
a. Elevated plasma aldosterone-to-renin ratio
b. Other features: Hypernatremia, hypokalemia, hypomagnesemia, glucose intolerance
c. Clinical presentation (can be asymptomatic)
i. Hypertension
ii. Muscle weakness/fatigue
iii. Headache
iv. Polydipsia
v. Nocturnal polyuria
3. Addison’s disease: Primary failure of the adrenal gland
a. Abnormal rapid cosyntropin (synthetic ACTH) stimulation test (blunted increase in cortisol
concentrations) suggests adrenal insufficiency.
b. Clinical presentation
i. Hyperpigmentation (caused by elevated ACTH concentrations)
ii. Weight loss
iii. Dehydration
iv. Hyponatremia, hyperkalemia, elevated BUN (blood urea nitrogen)
C. Therapy Goals – For all, reduce morbidity and mortality and eliminate cause.
1. Reversal of clinical features
2. Normalization of biochemical changes (when possible)
3. Long-term control without recurrence (remission when possible)
D. Pharmacotherapy
1. Cushing’s syndrome: Surgical resection of causative area/tumor is usual treatment of choice.
Pharmacotherapy usually reserved for the same criteria listed above for pituitary adenomas
a. Ketoconazole
i. Mechanism of action: In addition to its antifungal activity, it hinders cortisol production by
inhibition of 11- and 17-hydroxylase.
ii. Dosing
(a) Initial: 200 mg 2 times/day by mouth
(b) Maximal: 400 mg 3 times/day
iii. Adverse effects
(a) Gynecomastia
(b) Abdominal discomfort
(c) Reversible hepatic transaminase elevations
b. Mitotane
i. Mechanism of action: Inhibits 11-hydroxylase but also has some direct adrenolytic activity
ii. Dosing
(a) Initial: 500–1000 mg/day by mouth (some use much higher daily doses, but they are not
well tolerated)
(b) Maximal: 9–12 g/day
iii. Adverse effects
(a) Anorexia
(b) Ataxia
(c) Abdominal discomfort
(d) Lethargy
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c. Etomidate
i. Mechanism of action: Similar to ketoconazole, inhibits 11-hydroxylase
ii. Dosing
(a) Initial: 0.03 mg/kg intravenously followed by a 0.1-mg/kg/hour infusion
(b) Maximal: 0.3 mg/kg/hour
iii. Given route of administration is usually reserved for situations in which rapid control of
cortisol levels is required and oral therapy is problematic.
d. Metyrapone (by compassionate use only)
i. Mechanism of action: Hinders secretion of cortisol by blocking final step in cortisol synthesis
through inhibition of 11-hydroxylase activity
ii. Dosing
(a) Initial: 500 mg 3 times/day by mouth
(b) Average dose in Cushing’s syndrome is 2000 mg/day, but it is about 4000 mg in ectopic
ACTH syndrome.
iii. Adverse effects
(a) Hypoadrenalism
(b) Hypertension
(c) Worsening of hirsutism and acne if present before treatment
(d) Headache
(e) Abdominal discomfort
e. Efficacy is measured by control of symptoms and normalization of 24-hour urine-free cortisol
concentrations.
2. Hyperaldosteronism
a. Spironolactone (drug of choice)
i. Mechanism of action: Competitively inhibits aldosterone biosynthesis
ii. Dosing
(a) Initial: 25–50 mg/day by mouth
(b) Maximal: 400 mg/day
iii. Adverse effects
(a) Hyperkalemia
(b) Gynecomastia
(c) Abdominal discomfort
b. Eplerenone and amiloride are alternatives to spironolactone.
3. Addison’s disease
a. Steroid replacement (replace cortisol loss)
i. Oral administration is commonly dosed to mimic normal cortisol production circadian
rhythm.
ii. Two-thirds administered in the morning and one-third in the evening
(a) This may cause periods of transient adrenal insufficiency and/or variable serum
concentrations in some patients.
(b) Daily cortisol production in average patient: 5–10 mg/m2
b. Hydrocortisone: 15 mg/day (may negate need for fludrocortisone compared with using cortisone
or prednisone)
i. Cortisone acetate: 20 mg/day
ii. Prednisone: 2.5 mg/day
iii. Dexamethasone: 0.25–0.75 mg/day
c. Fludrocortisone (replaces loss of mineralocorticoid): 0.05–0.2 mg/day by mouth
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d. For women with decreased libido or low energy levels because of androgen deficiency: DHEA
(dehydroepiandrosterone): 25–50 mg/day
e. Efficacy can be measured by symptom improvement.
f. Note that, during times of stress/illness, corticosteroid doses will need to be increased. Dosage and
route of administration depend on level of stress to the body.
IV. OBESITY
A. Classification
1. Based on BMI in kilograms per square meter
2. Normal: BMI 18.5–24.9
3. Overweight: BMI 25.0–29.9
4. Obesity
a. Class I: BMI 30.0–34.9
b. Class II: BMI 35.0–39.9
c. Class III: BMI of 40 or greater
B. Therapy Goals
1. Reduce weight: 10% weight loss can be initial goal over about 6 months.
2. Maintain lower weight long term.
3. Limit weight-induced comorbidities (e.g., type 2 DM, cardiovascular disease).
C. Nonpharmacologic Therapy
1. Increased physical activity
a. Initially, moderate activity for 30–45 minutes, 3–5 times a week
b. Institute of Medicine recommends 1 hour/day of moderately intensive exercise.
2. Dietary options
a. Reduced-caloric intake/low-fat diet
i. 1200–1800 kcal/day
ii. Less than 30% of calories from fat
b. Low-carbohydrate diet
i. Increased fat and protein at the expense of carbohydrates
ii. Faster reduction in weight compared with low-fat diets, but overall weight reduction is similar
after 1–2 years
iii. Has beneficial effect on lipids compared with low-fat diets
iv. Vegetable-based fat source associated with lower mortality compared with animal-based fat source
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3. Surgery: Usually reserved for severely obese (BMI greater than 40) or lower BMIs with existing
comorbidities
a. Gastric bypass
b. Gastric banding
D. Pharmacotherapy
1. In conjunction with diet, physical activity, and behavior therapy
2. Should be reserved for those not achieving adequate lifestyle modifications, those who are obese
(consider in overweight patients with significant comorbidities [e.g., diabetes, cardiovascular disease])
3. Orlistat
a. Mechanism of action: Reduced absorption of fat by inhibition of gastric and pancreatic lipases
b. Dosing
i. Prescription (Xenical): 120 mg 3 times/day during or up to 1 hour after meals
ii. Over the counter (Alli): 60 mg 3 times/day during or up to 1 hour after meals
c. Adverse effects
i. GI tract: Flatulence, oily stool, loose stool, fecal urgency/incontinence (very dependent on fat
content of meal)
ii. Reduced absorption of fat-soluble vitamins (A, D, E, and K): Use vitamin supplement before
or well after use.
iii. Hepatotoxicity: 2010 U.S. Food and Drug Administration (FDA) Drug Safety Communication
on severe liver injury with prescription product
4. Diethylpropion
a. Mechanism of action: Increased central nervous system release of norepinephrine and dopamine.
Schedule IV
b. Dosing: 25 mg 3 times/day (immediate-release formulation) or 75 mg once daily (controlled-
release formulation)
c. Adverse effects: Increased blood pressure, constipation, increased heart rate, dysrhythmias, abuse
potential (avoid in patients with hypertension or history of cardiovascular disease)
5. Phentermine
a. Mechanism of action: sympathomimetic. Schedule IV
b. Dosing: Dependent on formulation (capsule, tablet, or disintegrating tablet)
c. Limited therapy duration of up to 3 months recommended
d. Adverse effects: Similar to diethylpropion above, abuse potential
6. Off-label medications used, although not well studied specifically for obesity: Exenatide, selective
serotonin reuptake inhibitors, bupropion with or without naltrexone, zonisamide, topiramate with or
without phentermine, metformin, pramlintide
A. Background/Classification
1. May be a cause of infertility in up to 20% of infertile couples
2. Mainly considered a condition caused by androgen excess or hyperandrogenism
3. Underlying cause appears to be insulin resistance (in obese and nonobese patients) with subsequent
compensatory insulin hypersecretion or increased insulin action. This increased action stimulates
androgen secretion by the ovaries and/or adrenal cells, leading to increased luteinizing hormone
(LH) secretion but normal or low FSH levels with a subsequent decrease in follicular maturation and
anovulation.
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B. Diagnosis
1. Still somewhat under debate, no clear consensus
2. 1990 National Institutes of Health (NIH) criteria
a. Hyperandrogenism and/or hyperandrogenemia
b. Oligoovulation (infrequent or irregular ovulation)
c. Exclusion of other secondary causes, particularly adrenal hyperplasia, Cushing’s syndrome,
hyperprolactinemia
3. 2003 Rotterdam criteria: Presence of at least two of the following and ruling out secondary causes:
a. Menstrual irregularity (oligo- and/or anovulation)
b. Hyperandrogenism (clinical or biochemical signs)
c. Polycystic ovaries (by transvaginal ultrasound)
4. 2006 Androgen Excess Society: Follow 1990 NIH criteria, but recognize concerns brought about from
the Rotterdam criteria.
C. Clinical Presentation
1. Clinical signs of hyperandrogenism: Hirsutism, acne, pattern alopecia (can vary by ethnicity)
2. Biochemical signs of hyperandrogenism (should not be used as sole criteria because 20%–40% of
patients with PCOS may be in the normal range):
a. Elevated free or total serum testosterone
b. Increased LH/FSH ratio greater than 2
3. Infrequent, irregular (e.g., late), or no ovulation leading to irregular menses
4. Infertility despite unprotected and frequent intercourse during the past year
5. In obese patients, prediabetes (impaired glucose tolerance) or type 2 DM may be present.
D. Therapy Goals
1. Normalize ovulation/menses.
2. Improve fertility in those who wish to become pregnant.
3. Limit clinical signs.
4. Reduce progression to type 2 DM (perhaps cardiovascular disease).
E. Nonpharmacologic Therapy: Weight loss (5%–10%) is the therapy of choice in overweight/obese patients.
F. Pharmacotherapy
1. If goal is to improve fertility
a. Clomiphene citrate
i. Mechanism of action: Induces ovulation as a selective estrogen receptor modulator that
improves LH-FSH secretion
ii. Dosing
(a) 50 mg/day for 5 days starting on the third or fifth day of the menstrual cycle
(b) Increase to 100 mg if ovulation does not occur after first cycle of treatment.
(c) Maximal daily dose 150–200 mg/day
iii. Adverse effects: Flushing, GI discomfort, vision disturbances, vaginal dryness, multiple
pregnancies
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A. Consensus Recommendations
1. American Diabetes Association (ADA). Updated yearly in the January supplement of Diabetes Care
(www.diabetes.org)
2. American College of Endocrinology/American Association of Clinical Endocrinologists (ACE/AACE)
3. Canadian Diabetes Association
4. Various European groups
5. For the remainder of this section, unless otherwise noted, the ADA recommendations will be followed.
B. Classification
1. Type 1 DM
a. Attributable to cellular-mediated β-cell destruction leading to insulin deficiency (insulin required
for survival)
b. Accounts for 5%–10% of DM
c. Formerly known as insulin-dependent diabetes, juvenile-onset diabetes
d. Prevalence in the United States: 0.12% (about 340,000)
e. Usually presents in childhood or early adulthood but can present in any stage of life
f. Usually symptomatic with a rapid onset in childhood but can be slower in older adults
2. Type 2 DM
a. Result of insulin resistance with subsequent defect in insulin secretion
b. Accounts for 90%–95% of DM
c. Formerly known as non–insulin-dependent diabetes, adult-onset diabetes
d. Prevalence in the United States: 7.8% (about 23.6 million and growing!)
e. Often relatively asymptomatic with a slow onset over 5–10 years. Rationale for early, frequent
screening of those at risk (below) and initial assessment for complications at diagnosis
f. Disturbing increased trends in type 2 DM in children and adolescents attributed to rise in obesity
3. Maturity-onset diabetes of the young (MODY)
a. Result of genetic disorder leading to impaired secretion of insulin with little or no impairment in
insulin action
b. Onset usually before age 25 and may mimic either type 1 or 2 DM
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4. Gestational diabetes
a. Glucose intolerance occurring during pregnancy
b. Prevalence: 1%–14% of pregnancies (complicates about 4% of pregnancies)
c. New diagnostic criteria (see below) will likely improve the diagnosis and change the prevalence.
d. Most common in third trimester
5. Prediabetes
a. Impaired glucose tolerance (IGT)
b. Impaired fasting glucose (IFG)
6. Other DM types
a. Genetic defects in β-cell function or insulin action
b. Diseases of the pancreas (e.g., pancreatitis, neoplasia, cystic fibrosis)
c. Drug or chemical induced (e.g., glucocorticoids, nicotinic acid, protease inhibitors, atypical
antipsychotics)
Patient Case
6. A 64-year-old African American woman has had a 12-kg (27 lb) weight increase during the past year, pri-
marily because of inactivity and a poor diet. Her BMI is 44 kg/m 2. Her mother and sister both have type 2
DM. Her fasting glucose concentration today is 212 mg/dL. Which one of the following is the best course of
action?
A. Diagnose type 2 DM and begin treatment.
B. Diagnose type 1 DM and begin treatment.
C. Obtain another glucose concentration today.
D. Obtain another glucose concentration another day.
C. Screening for DM
1. Type 1 DM:
a. Symptomatic patients
b. Asymptomatic patients at higher risk
i. History of transient hyperglycemia or relatives with type 1 DM
ii. Measure islet autoantibodies to assess risk of type 1 DM.
2. Type 2 DM
a. Age 45 or older, repeat every 3 years if normal
b. Start younger if BMI is 25 kg/m2 or greater and at least one of the following risk factors:
i. History of cardiovascular disease
ii. Impaired glucose tolerance or impaired fasting glucose
iii. History of PCOS
iv. HDL-C less than 35 mg/dL and/or TG greater than 250 mg/dL
v. Hypertension
vi. Women with a diagnosis of gestational diabetes or women who delivered a baby weighing
more than 4.1 kg (9 lb)
vii. High-risk ethnicity: African American, Latino, Native American, Asian American, Pacific
Islander
viii. First-degree relative with type 2 DM
ix. Physical inactivity
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3. Gestational DM
a. Screen at first prenatal visit for undiagnosed type 2 DM in all patients with type 2 DM risk factors
present.
b. Screen at 24–28 weeks of gestation using a 75-g OGTT.
c. If a diagnosis of gestational DM is made, screen for diabetes 6–12 weeks after delivery.
D. DM Diagnosis
1. Type 1 and 2 DM diagnosis
a. Glycemic parameters in nonpregnant patients
i. Fasting plasma glucose
(a) Easy and preferred method
(b) 126 mg/dL or greater
ii. Random plasma glucose
(a) 200 mg/dL or greater with symptoms of hyperglycemia
(b) Common hyperglycemia symptoms include polyuria, polydipsia, and unexplained weight
loss
(c) Prudent to verify with A1c concentration
iii. Oral glucose tolerance test
(a) Plasma glucose concentration obtained 2 hours after a 75-g oral glucose ingestion
(b) 200 mg/dL or greater
(c) More sensitive and specific than FPG but more cumbersome to perform
iv. With an abnormal test result, the patient should be tested again (preferably with the same test,
but it can be any of the above on a subsequent day or by obtaining an A1c unless unequivocal
hyperglycemia is noted).
v. A1c (glycated hemoglobin)
(a) 6.5% or greater
(b) Confirmed by repeating (unless unequivocal hyperglycemia is noted), though interval for
repeating test is not provided
(c) May be less sensitive than FPG in identifying mild diabetes but does not require fasting
and has less variability from day to day
(d) A1c values may be inaccurate in patients with hemolytic anemia, chronic malaria, sickle
cell anemia, or significant blood loss and/or recent blood transfusion.
b. Other useful diagnostic tests if type of DM present is in question
i. C-peptide (measure of endogenous insulin secretion, usually negligible in type 1 DM and
normal or elevated in type 2 DM)
ii. Presence of islet cell autoantibodies, autoantibodies to insulin, glutamic acid decarboxylase,
or tyrosine phosphatase (all suggest autoimmune activity)
2. Gestational diabetes diagnosis: Glycemic parameters in pregnancy
a. 2011 ADA updated and simplified diagnosis criteria
b. 75-g OGTT at weeks 24–28 of gestation
i. Fasting: 92 mg/dL or greater
ii. 1 hour post-OGTT: 180 mg/dL or greater
iii. 2 hours post-OGTT: 153 mg/dL or greater
3. Prediabetes diagnosis (high-risk population)
a. Impaired fasting glucose: FPG between 100 and 125 mg/dL
b. Impaired glucose tolerance: 2-hour plasma glucose post-OGTT (75 g) between 140 and 199 mg/dL
c. A1c between 5.7% and 6.4%
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Patient Case
7. A 56-year-old man was recently given a diagnosis of type 2 DM. He does not have other chronic diseases or
history of cardiovascular disease. Which one of the following sets of values is the best selection of goals for
his A1c, blood pressure, and LDL-C?
A. A1c less than 6.0%, blood pressure less than 120/80 mm Hg, LDL-C less than 70 mg/dL.
B. A1c less than 7.0%, blood pressure less than 130/80 mm Hg, LDL less than 100 mg/dL.
C. A1c less than 6.5%, blood pressure less than 140/90 mm Hg, LDL less than 130 mg/dL.
D. A1c less than 8.0%, blood pressure less than 130/85 mm Hg, LDL-C less than 160 mg/dL.
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Patient Case
8. A 52-year-old woman has received a diagnosis today of type 2 DM. Her A1c today is 7.8% and her FBG today
is 186 mg/dL. She has no other chronic disease states or history of cardiovascular disease. According to the
current ADA guidelines, which one of the following would be considered the best initial treatment of choice
for this patient?
A. Implement changes in lifestyle (diet and exercise).
B. Implement changes in lifestyle (diet and exercise) plus metformin 500 mg once daily.
C. Implement changes in lifestyle (diet and exercise) plus sitagliptin 100 mg once daily.
D. Implement changes in lifestyle (diet and exercise) plus insulin glargine 10 units once daily.
9. A 66-year-old man has had type 2 DM for 4 years and has a history of pancreatitis. His A1c today is 7.7%.
He has altered his diet, and he states that he has been exercising regularly for months now. His currently
is receiving metformin 1000 mg twice daily. Which one of the following would be the best choice to help
optimize his glycemic control?
A. Continue current medications and counsel to improve his diet and exercise.
B. Discontinue metformin and initiate exenatide 5 mcg twice daily.
C. Add sitagliptin 100 mg once daily to his metformin therapy.
D. Add glyburide 5 mg twice daily to his metformin therapy.
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d. Adverse effects
i. Common: Hypoglycemia, weight gain
ii. Less common: Rash, headache, nausea, vomiting, photosensitivity
e. Contraindications/precautions
i. Hypersensitivity to sulfonamides
ii. Patients with hypoglycemic unawareness
iii. Poor renal function (glipizide may be a better option than glyburide or glimepiride in elderly
patients or in those with renal impairment because drug or active metabolites are not renally
eliminated)
f. Efficacy
i. 1%–2% A1c reduction
ii. Note: For this and all medications used to treat hyperglycemia, the absolute decrease in A1c is
larger for higher baseline A1c values and smaller for lower A1c values.
2. Metformin (biguanide)
a. Mechanism of action: Reduces hepatic gluconeogenesis. Also has favorable effects on insulin
sensitivity and intestinal absorption of glucose
b. Dosing
i. Initial: 500 mg once or twice daily (once daily with extended-release formulation)
ii. Maximal daily dose: 2550 mg (more commonly 2000 mg/day)
iii. Can increase at weekly intervals as necessary
iv. Small initial dosage and slow titration secondary to GI disturbances
c. Adverse effects
i. Common: Nausea, vomiting, diarrhea, epigastric pain
ii. Less common: Decrease in vitamin B12 levels, lactic acidosis (rare)
iii. Signs or symptoms of lactic acidosis include acidosis, nausea, vomiting, increased respiratory
rate, abdominal pain, shock, and tachycardia.
d. Contraindications/precautions (because of risk of lactic acidosis)
i. Renal impairment: Serum creatinine 1.5 mg/dL or greater in men and 1.4 mg/dL or greater in
women or reduced creatinine clearance (CrCl; CrCl cutoff is not well established, but it may
be as low as 30 mL/minute). Renal insufficiency increases risk of lactic acidosis.
ii. Age 80 years or older
iii. High risk of cardiovascular event or hypoxic state
iv. Hepatic impairment
v. Congestive heart failure (especially if prone to exacerbations)
vi. Interrupt therapy if undergoing procedures using iodinated contrast dye because of risk of
nephrotoxicity. Reinitiate after 48 hours and after normal serum creatinine concentrations are
achieved.
e. Efficacy:
i. 1%–2% A1c reduction
ii. Some benefit in TG reduction and weight loss
iii. Considered first-line therapy unless contraindicated on the basis of adverse effect profile,
reduction in A1c, cost, and limited data that it reduces cardiovascular events in overweight
patients
3. Meglitinides
a. Mechanism of action: Very similar to that of sulfonylureas in increasing insulin secretion from the
pancreas but with a more rapid onset and shorter duration of activity
b. Glucose-dependent activity
c. Two currently available: Repaglinide and nateglinide
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d. Dosing
i. Repaglinide
(a) Initial: 0.5–1 mg 15 minutes before meals
(b) Maximal daily dose: 16 mg
ii. Nateglinide
(a) 120 mg before meals
(b) 60 mg if A1c near goal
iii. Repaglinide can be increased in weekly intervals if needed.
e. Adverse effects: Hypoglycemia (though less than with sulfonylureas), weight gain, upper
respiratory infection
f. Contraindications/precautions
i. Hypersensitivity
ii. Caution in concomitant use of repaglinide and gemfibrozil, can lead to greatly increased
repaglinide levels
g. Efficacy:
i. 0.5%–1.5% A1c reduction (repaglinide shown to reduce A1c more than nateglinide)
ii. Most effective on postprandial glucose excursions
4. Thiazolidinediones (often called TZDs or glitazones)
a. Mechanism of action
i. Peroxisome proliferator-activated receptor γ agonist
ii. Increases expression of genes responsible for glucose metabolism, resulting in improved
insulin sensitivity
b. Two agents available: Pioglitazone and rosiglitazone
i. In September 2010, the FDA initiated restricted access to rosiglitazone secondary to continued
concerns about its cardiovascular safety.
ii. Rosiglitazone is restricted to patients unable to obtain glycemic control with other agents and
when pioglitazone is not used for medical reasons.
c. Dosing
i. Pioglitazone
(a) Initial: 15 mg once daily
(b) Maximal daily dose: 45 mg
ii. Rosiglitazone
(a) Initial: 1–2 mg once daily
(b) Maximal daily dose: 8 mg
iii. Dose titration is slower with these agents, and the maximal effect of a dose change may not be
observed for 8–12 weeks.
d. Adverse effects
i. Weight gain
ii. Fluid retention (particularly peripheral edema), worse with insulin use (manufacturer of
rosiglitazone states to use it no longer with insulin). Edema less responsive to diuretic therapy
iii. Risk of bone fractures
iv. Pioglitazone associated with small risk of bladder cancer (recent updated label information)
v. Increased risk of heart failure
(a) Both have a black box warning.
(b) More than 2-fold higher relative risk, though absolute risk is quite small
vi. Both agents have been withdrawn from European Union
vii. Risk Evaluation and Mitigation Strategy (REMS) in the United States with rosiglitazone
(a) Although not pulled from the U.S. market, REMS drastically reduces those who will be
able to obtain it.
(b) See end of chapter for more detail on REMS.
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e. Contraindications/precautions
i. Hepatic impairment
ii. Class III/IV heart failure
iii. Existing fluid retention
f. Efficacy
i. 0.5%–1.4% A1c reduction
ii. Both drugs increase HDL-C, but pioglitazone has a more favorable effect in reducing LDL-C
and TG compared with rosiglitazone.
5. α-Glucosidase inhibitors
a. Mechanism of action: Slows the absorption of glucose from the intestine into the bloodstream by
slowing the breakdown of large carbohydrates into smaller absorbable sugars
b. Two agents available: Acarbose and miglitol
c. Dosing (both agents dosed similarly)
i. Initial: 25 mg 3 times/day at each meal
ii. Maximal daily dose: 300 mg
iii. Slow titration, increasing as tolerated every 4–8 weeks to minimize GI adverse effects
d. Adverse effects
i. Flatulence, diarrhea, abdominal pain
ii. Increased liver enzymes observed with high doses of acarbose
e. Contraindications/precautions: Inflammatory bowel disease, colonic ulcerations, intestinal obstruction
f. Efficacy
i. 0.5%–0.8% reduction in A1c
ii. Targets postprandial glucose excursions
iii. May not be as effective in patients using low-carbohydrate diets
6. Dipeptidyl peptidase-4 (DPP-4) inhibitors
a. Mechanism of action: Inhibits the breakdown of glucagon-like peptide-1 (GLP-1) secreted during
meals, which in turn increases pancreatic insulin secretion, limits glucagon secretion, slows gastric
emptying, and promotes satiety
b. Dosing
i. Sitagliptin: 100 mg once daily
(a) Reduce dose with CrCl between 30 and 50 mL/minute to 50 mg once daily.
(b) Reduce dose with CrCl less than 30 mL/minute to 25 mg once daily.
ii. Saxagliptin: 5 mg once daily. (Reduce with CrCl equal to 50 mL/minute or less to 2.5 mg
once daily.)
iii. Linagliptin: 5 mg once daily (no dosage adjustment for renal impairment)
iv. Vildagliptin approved in Europe and Asia; seeking U.S. approval. Alogliptin seeking U.S. approval
c. Adverse effects
i. Upper respiratory and urinary tract infections, headache
ii. Hypoglycemia with monotherapy is minimal, but increased frequency with concurrent
sulfonylurea therapy (can lower dose of sulfonylurea when initiating)
iii. Sitagliptin has had some postmarketing reports of acute pancreatitis, angioedema, Stevens-
Johnson syndrome, and anaphylaxis.
d. Contraindications/precautions
i. Previous hypersensitivity to the agents
ii. History of pancreatitis
e. Efficacy: 0.5%–0.8% reduction in A1c
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Patient Case
10. A 66-year-old man is given a diagnosis of type 2 DM today. His A1c was 8.2%, and his serum creatinine
was 1.8 mg/dL 2 weeks ago. He has a history of hypertension, dyslipidemia, and systolic heart failure (New
York Heart Association class III, ejection fraction 33%). He has 2+ pitting edema bilaterally. In addition to
improvements in diet and exercise, which one of the following is the best drug to initiate?
A. Metformin.
B. Pioglitazone.
C. Glipizide.
D. Sitagliptin.
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I. Incretin Analogs
1. GLP-1 analog
a. Mechanism of action: Synthetic analog of human GLP-1 that binds to GLP-1 receptors, resulting
in glucose-dependent insulin secretion, reduction in glucagon secretion, and reduced gastric
emptying; promotes satiety
b. Two agents available (exenatide and liraglutide)
c. Dosing
i. Exenatide
(a) Initial: 5 mcg subcutaneously twice daily, administered no more than 60 minutes before
morning and evening meals
(b) Maximal daily dose: 20 mcg/day
(c) Dose titration from 5 to 10 mcg twice daily after 1 month if tolerated
(d) Once-weekly formulation approved in Europe and likely to gain approval in the United
States
ii. Liraglutide
(a) 0.6 mg subcutaneously once daily for 1 week (regardless of mealtime)
(b) Dose titration from 0.6 to 1.2 mg/day if tolerated
(c) Maximal daily dose: 1.8 mg/day
iii. Both agents available in prefilled, multidose syringes
d. Adverse effects
i. Nausea, vomiting, diarrhea very common
ii. Hypoglycemia common with concurrent sulfonylurea (consider reduction in sulfonylurea dose
if adding exenatide)
iii. Postmarketing reports of pancreatitis, acute renal failure, or impairment
e. Contraindications/precautions
i. Impaired renal function: CrCl less than 30 mL/minute
ii. History of severe GI tract disorder
iii. History of pancreatitis
iv. For liraglutide: Contraindicated in patients with a personal or family history of medullary
thyroid carcinoma (adverse effect found in rodent studies but not in humans)
f. Efficacy
i. A 0.5%–1.1% reduction in A1c
ii. Effects on postprandial hyperglycemia better than on fasting glucose concentrations
iii. Modest weight loss
2. Amylin analog
a. Mechanism of action: Amylin is cosecreted with insulin and has effects similar to GLP-1 described
above.
b. Pramlintide is currently the only agent in this class available in the United States. Can be used in
either type 1 or type 2 DM as adjunctive therapy in patients receiving insulin
c. Dosing
i. Type 1 DM
(a) Initial: 15 mcg subcutaneously immediately before main meals
(b) Must reduce dose of preprandial rapid-acting, short-acting, or combination insulin
products by 50%
(c) Maximal daily dose: 60 mcg with each meal
(d) Dose should be titrated in 15-mcg increments, as tolerated, no more rapidly than
every 3 days.
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ii. Type 2 DM
(a) Initial: 60 mcg subcutaneously immediately before main meals
(b) As above, must reduce preprandial insulins by 50%
(c) Maximal daily dose: 120 mcg with each meal
(d) Dose should be titrated in 60-mcg increments, as tolerated, no more rapidly than every
3–7 days.
iii. Use of prefilled pens is strongly recommended when possible versus using a syringe and vial to
reduce risk of dosing errors (dosing instructions with U-100 syringes and vial in package insert).
iv. Cannot be mixed with insulin products, requires increased frequency of daily injections
d. Adverse effects
i. Black box warning for severe hypoglycemia, especially in patients with type 1 DM
ii. Nausea, vomiting, anorexia, headache
e. Contraindications/precautions
i. Substantial gastroparesis
ii. History of poor adherence or monitoring of BG
iii. A1c greater than 9%
iv. Hypoglycemia unawareness or frequent bouts of hypoglycemia
f. Efficacy
i. A 0.5%–1% reduction in A1c
ii. Very effective at controlling postprandial glucose excursions
J. Insulin
1. Categorized on the basis of duration after injection
a. Short acting: Regular human insulin
b. Rapid acting: Insulin aspart, lispro, and glulisine
c. Intermediate acting: Neutral protamine Hagedorn (NPH)
d. Long acting: Insulin glargine and detemir; cannot be mixed with other insulins
2. Combination products (NPH/either regular or rapid-acting insulin): 70/30, 75/25
3. Glycemic target
a. Regular- and short-acting insulins target postprandial glucose concentrations.
b. Intermediate- and long-acting insulins target fasting glucose concentrations.
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Patient Case
11. A male patient with an A1c of 7.6% is receiving insulin detemir (60 units once daily at bedtime) and insulin
lispro (6 units before breakfast, 5 units before lunch, and 8 units before dinner). His morning FPG concen-
trations have consistently been high for the past 3 weeks, averaging 160 mg/dL. He reports no daytime or
nighttime hypoglycemia. Which one of the following is the best insulin adjustment to improve his overall
glycemic control?
A. Increase his dinnertime lispro to 10 units.
B. Decrease his dinnertime lispro to 6 units.
C. Increase his bedtime detemir to 65 units.
D. Decrease his bedtime detemir to 55 units.
12. A patient weighing 110 lb has been given a diagnosis of type 1 DM. The physician wishes to start at a TDI
of 0.4 unit/kg/day with a combination of long- and rapid-acting insulin. The patient is unwilling to estimate
his or her carbohydrate intake at this time. Which one of the following would be the most appropriate initial
basal insulin regimen?
A. 20 units of insulin glargine once daily.
B. 20 units of insulin detemir once daily.
C. 10 units of insulin aspart once daily.
D. 10 units of insulin glargine once daily.
13. A patient with type 1 DM has been initiated with basal/bolus insulin therapy. The patient receives 13 units
once daily of insulin detemir. The patient is also receiving insulin lispro, 4 units before breakfast, 3 units
before lunch, and 4 units before dinner. You are to initiate a correctional dosing strategy for the patient.
Which of the following is the best estimate for the milligram per deciliter decrease in BG 1 unit of lispro
that may be obtained?
A. 25 mg/dL.
B. 50 mg/dL.
C. 75 mg/dL.
D. 85 mg/dL.
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a. Step 1: As above
b. Step 2: Either a or b below
i. Add pioglitazone.
(a) If inadequate control, add sulfonylurea
(b) If inadequate control with metformin-pioglitazone-sulfonylurea, change to metformin-
basal insulin combination
ii. Add exenatide. If inadequate control, change to metformin-pioglitazone-sulfonylurea
combination or change to metformin-basal insulin combination
c. Step 3: As above
4. Initial insulin therapy: Use insulin early with any of the following baseline characteristics:
a. A1c greater than 10%
b. Random glucose greater than 300 mg/dL or fasting glucose greater than 250 mg/dL
c. Hyperglycemic symptoms
d. Presence of urine ketones
5. Changing from oral DM medications to insulin-only management (e.g., because of adverse effects,
contraindications, lack of efficacy of oral medications)
a. Can follow NPH/regular insulin or basal/bolus approach similar to that in type 1 DM described above
b. The TDI requirements in type 2 DM are usually higher than in type 1 DM because of insulin resistance.
6. Changing from NPH to long-acting insulin (either insulin glargine or detemir)
a. If adequate glycemic control already obtained, initiate insulin glargine at 80% of total daily NPH dose
b. Detemir may be initiated on a unit-to-unit basis and may require higher daily insulin dosages after
conversion, but this is determined by glycemic response.
A. Hypoglycemia
1. Degree of intervention depends on glucose concentrations and presence of symptoms.
2. Symptoms are very patient-specific.
3. Definition: Plasma glucose less than 70 mg/dL with or without symptoms
4. Mild to moderate hypoglycemia
a. Oral ingestion of 15–20 g of glucose or equivalent
b. Repeat glucose concentration in 15 minutes and, if still less than 70 mg/dL, repeat.
5. Severe hypoglycemia (altered consciousness, requires assistance from others)
a. Glucagon 1 mg intramuscularly
b. Intravenous dextrose if patient does not respond to glucagon
B. Diabetic Ketoacidosis
1. More common in type 1 DM but can occur in type 2 DM
2. Usually occurs because of a precipitating factor that considerably stresses the body, resulting in
increased counterregulatory hormones
a. Inappropriate (including nonadherence) or inadequate insulin therapy and infection are the two
most common causes.
b. Other causes: Myocardial infarction, pancreatitis, stroke, drugs (e.g., corticosteroids)
3. Results in significant hyperglycemia, dehydration, and ketoacidosis
4. Common signs/symptoms: Polyuria, polydipsia, vomiting, dehydration, weakness, altered mental
status, coma, abdominal pain, Kussmaul respirations, tachycardia, hyponatremia, hyperkalemia
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5. Treatment
a. Treat underlying cause if known.
b. Fluid replacement
i. 0.45%–0.9% sodium chloride depending on baseline serum sodium concentrations
ii. Change to 5% dextrose with 0.45% sodium chloride when serum glucose is less than 200 mg/dL.
c. Insulin
i. Goal is to stop ketosis, not to normalize glucose concentrations.
ii. Intravenous bolus: 0.1 unit/kg
iii. Intravenous infusion:
(a) 0.1 unit/kg/hour (increase if not a 50- to 75-mg/dL drop in serum glucose in the first hour)
(b) Alternatively, 0.14 unit/kg/hour if no insulin bolus is given
(c) If not at least a 10% decrease in serum glucose obtained in first hour, give 0.14 unit/kg
intravenous bolus
(d) Reduce infusion rate to 0.02–0.05 unit/kg/hour when serum glucose reaches 200 mg/dL,
and keep glucose between 150 and 200 mg/dL until DKA resolves.
iv. Interrupt insulin treatment if baseline serum potassium is less than 3.3 mEq/L and until corrected.
d. Potassium
i. 20–30 mEq/L of intravenous fluid if baseline serum potassium greater than 3.3 but less than
5.3 mEq/L
ii. Hold if 5.3 mEq/L or greater initially. Monitor and replace as needed.
iii. 20–30 mEq potassium per hour if baseline less than 3.3 mEq/L (while holding insulin)
e. Intravenous bicarbonate if serum pH less than 6.9
f. DKA considered resolved and can be converted to subcutaneous insulin when serum glucose is
less than 200 mg/dL and at least two of the following:
i. Venous pH is greater than 7.3.
ii. Serum bicarbonate is 15 mEq/L or greater.
iii. Calculated anion gap of 12 mEq/L or less
C. Nephropathy
1. Screen annually with random spot collection of urine albumin-to -creatinine ratio starting at diagnosis
in type 2 DM and after 5 or more years in type 1 DM.
a. Normal: Less than 30 mg/g (or micrograms per milligram)
b. Microalbuminuria: 30–299 mg/g
c. Macroalbuminuria: 300 mg/g or greater
2. Estimate CrCl yearly as well.
3. With type 1 DM, hypertension, and any degree of nephropathy: ACE inhibitor therapy
4. With type 2 DM, hypertension, and microalbuminuria: ACE inhibitor or ARB therapy
5. With type 2 DM, hypertension, macroalbuminuria, and serum creatinine greater than 1.5 mg/dL:
ARB therapy
6. The above differences in choice of drug class reflect what has been documented in the literature.
7. ACE inhibitors and ARBs are often used regardless of whether the patient has hypertension.
8. Dietary protein restriction as renal function declines
D. Retinopathy
1. Screen annually with dilated and comprehensive eye examinations starting at diagnosis in type 2 DM
and after 5 or more years in type 1 DM.
2. Frequency can be reduced to every 2–3 years after one or more normal examinations.
3. No specific pharmacotherapy recommended except to adequately control glucose concentrations and
blood pressure
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E. DM Neuropathies
1. Can have nerve damage in any area of the body
2. Screen for distal polyneuropathy using monofilament once yearly.
a. Screen after 5 years of type 1 DM and at diagnosis with type 2 DM.
b. Diminished sensitivity is a significant risk factor for diabetes-related foot ulcer and increases the
need for frequent visual inspection by patients if it exists.
3. Treatment of neuropathies is for symptomatic improvement and does not prevent progression.
4. Symptoms are patient-specific but may include numbness, burning, and tingling sensation.
5. Neuropathic pain
a. Tricyclic antidepressants (amitriptyline, desipramine)
i. Effective but limited because of anticholinergic effects (some recommend using secondary
amine tricyclic antidepressants (e.g., desipramine, nortriptyline) because they may have less
anticholinergic effect than tertiary amines (e.g., amitriptyline, imipramine)
ii. Daily dose is less than doses used for depression.
b. Anticonvulsants (gabapentin, lamotrigine, pregabalin)
i. Comparative data of gabapentin and pregabalin against tricyclic antidepressants show
similar efficacy with fewer adverse effects. Adverse effect profile is still significant (fatigue,
dizziness, etc.).
ii. Pregabalin is the only anticonvulsant approved for use in DM neuropathic pain and is also
recommended by the American Academy of Neurology in its 2011 guideline.
c. Selective serotonin reuptake inhibitor/selective serotonin and norepinephrine reuptake inhibitor
(duloxetine, paroxetine, citalopram)
i. Duloxetine only approved agent in this category
ii. Duloxetine comparative data with amitriptyline show similar efficacy and expected higher
anticholinergic adverse effects with amitriptyline.
d. Tramadol/acetaminophen: As effective as gabapentin, different adverse effect profile
6. Gastroparesis
a. Autonomic neuropathy causes considerable nausea/vomiting after meals because of delayed
gastric emptying.
b. Nonpharmacologic strategies
i. More frequent but smaller meals
ii. Homogenize food.
c. Pharmacologic treatment
i. Metoclopramide: 10 mg before meals: Risk of tardive dyskinesia or extrapyramidal reactions
ii. Erythromycin: 40–250 mg before meals
F. Cardiovascular Disease
1. Most common cause of morbidity and mortality as well as health care expenditures in DM complications
2. Proper DM management should always focus on cardiovascular disease risk reduction (review
Cardiovascular chapters).
3. Stress and continually assess blood pressure and lipid goals described above.
4. Blood pressure management
a. Given lower goal than for essential hypertension, often requires more antihypertensive medications
b. Hypertensive regimen should include an ACE inhibitor or ARB.
5. Lipid management
a. Assess fasting lipid profile annually.
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G. Preventive Immunizations
1. Annual influenza vaccine
2. Pneumococcal polysaccharide vaccine
B. In the wake of the rosiglitazone safety issue, the FDA now requires all newly approved diabetes
medications to prove cardiovascular safety.
1. At least 2 years of safety data that include cardiovascular events as an end point and independent
adjudication of events
2. Necessary to study in elderly patients, as well as in those with some degree of renal impairment and
those with more advanced diabetes
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REFERENCES
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thyroid disease: scientific review and guide- 3. Shalet S, Mukherjee A. Pharmacological treatment
lines for diagnosis and management. JAMA of hypercortisolism. Curr Opin Endocrinol Diabe-
2004;291:228–38. tes Obes 2008;15:234–8.
5. Sherman S, Talbert R. Thyroid disorders. In: 4. Vaughan E. Diseases of the adrenal gland. Med
DiPiro J, Talbert R, Yee G, Matzke G, Wells B, Clin North Am 2004;88:443–66.
Posey L, eds. Pharmacotherapy: A Pathophysi-
ologic Approach, 7th ed. New York: McGraw-Hill,
Obesity
2008:1243–64.
1. National Institutes of Health, National Heart, Lung,
6. Roos A, Linn-Rasker S, van Domburg R, Tijssen
Blood Institute. Clinical Guidelines on the Identi-
J, Berghout A. The starting dose of levothyroxine
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in primary hypothyroidism treatment. Arch Intern
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7. Pearce E, Farwell A, Braverman L. Thyroiditis. N
2. Foster G, Wyatt H, Hill J, et al. Weight and
Engl J Med 2005;348:2646–55.
metabolic outcomes after 2 years on a low-car-
8. Rodondi N, Newman A, Vittinghoff E, et al. Sub- bohydrate versus low-fat diet. Ann Intern Med
clinical hypothyroidism and the risk of heart fail- 2010;153:147–57.
ure, other cardiovascular events, and death. Arch
3. James W, Caterson I, Coutinho W, et al. Ef-
Intern Med 2005;165:2460–6.
fect of sibutramine on cardiovascular outcomes
9. Walsh J, Bremner A, Bulsara M, et al. Subclinical in overweight and obese subjects. N Engl J Med
thyroid dysfunction as a risk factor for cardiovas- 2010;363:905–17.
cular disease. Arch Intern Med 2005;165:2467–72.
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Polycystic Ovary
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cystic ovary syndrome. Lancet 2007;370:685–97.
Pituitary
2. Brassard M, AinMelk Y, Baillargeon J. Basic in-
1. Sheehan A, Yanovski J, Calis K. Pituitary gland fertility including polycystic ovary syndrome. Med
disorders. In: DiPiro J, Talbert R, Yee G, Matzke Clin North Am 2008;92:1163–92.
G, Wells B, Posey L, eds. Pharmacotherapy: A
3. Azziz R, Carmina E, Dewailly D, et al. Position
Pathophysiologic Approach, 7th ed. New York:
statement: criteria for defining polycystic ovary
McGraw-Hill, 2008:1281–95.
syndrome as a predominantly hyperandrogenic
2. Thorogood N, Baldeweg S. Pituitary disorders: an syndrome: an Androgen Excess Society guideline.
overview for the general physician. Br J Hosp Med J Clin Endocrinol Metab 2006;91:4237–45.
2008;69:198–204.
4. Nestler J. Metformin for the treatment of the
polycystic ovary syndrome. N Engl J Med
Adrenal 2008;358:47–54.
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1. Answer: A 5. Answer: D
This patient has hypothyroidism on the basis of her Because the aldosterone-to-renin ratio and blood pres-
elevated TSH and low free T4 caused by Hashimoto’s sure are high, hyperaldosteronism is the most likely
disease. Levothyroxine is the drug of choice for this disease listed. Cushing’s syndrome and hyperaldoste-
condition given its adverse effect profile, cost, antige- ronism can be secondary causes of hypertension. In this
nicity profile, and uniform potency. Although liothy- case, the patient’s free 24-hour urine cortisol is normal
ronine can be used for hypothyroidism, its potential but would be elevated if he had Cushing’s syndrome;
for increasing the risk of cardiovascular complications thus, Answer A is incorrect. Answer B is incorrect be-
makes it second line (Answer B). Answer C is also in- cause Addison’s disease is a result of cortisol deficiency
correct given its increased antigenicity compared with and is not associated with hypertension. Answer C, hy-
levothyroxine. Answer D is incorrect because it is an perprolactinemia, is unlikely, given the patient’s pre-
agent used to treat hyperthyroidism. sentation and his abnormal aldosterone-to-renin ratio.
2. Answer: D 6. Answer: D
Given this patient’s reluctance for ablative therapy, usu- Unless the patient has significant symptoms of hyper-
ally the most common treatment, oral therapy is war- glycemia (none noted in this case), a subsequent evalu-
ranted. Methimazole is recommended over PTU (An- ation for hyperglycemia by a fasting glucose concentra-
swer B) because it is associated with a lower risk of tion, a random glucose concentration, an OGTT, or an
hepatotoxicity, though it may not be more efficacious. A1c is warranted; hence, Answer A and Answer B are
Answer A is incorrect because iodine therapy is only incorrect. Answer C is incorrect because a subsequent
indicated in this type of case before surgery or during test for hyperglycemia should not be performed on the
an acute case of thyroid storm. Answer C is incorrect same day according to ADA guidelines.
because although β-blockers may provide some symp-
tomatic relief, they do little to stabilize this patient’s 7. Answer: B
thyroid levels. The goal A1c according to the ADA is less than 7.0%.
The goal blood pressure is less than 130/80 mm Hg,
3. Answer: A and the goal LDL-C is less than 100 mg/dL. The other
This patient’s TSH concentration is elevated well above answers all deviate from these goals in one fashion or
the reference range, whereas the free T4 concentration another.
is within normal limits. With mild symptoms of hypo-
thyroidism, this meets the criteria for subclinical hy- 8. Answer: B
pothyroidism. Most clinicians would treat her, ruling Changes in lifestyle modification, in addition to metfor-
out Answer C. Answer B and Answer D are incorrect min therapy, are preferred. Changes in lifestyle alone,
because this patient’s symptoms and TSH concentra- Answer A, although important, are no longer recom-
tion do not suggest hyperthyroidism. mended by the ADA. Answer C and Answer D are in-
correct because sitagliptin or insulin therapy as initial
4. Answer: D monotherapy is not recommended, though both would
Fluoxetine, a selective serotonin reuptake inhibitor, be effective in controlling BG levels. Metformin is pre-
may cause drug-induced hyperprolactinemia. Answer ferred given its safety profile, reduction in A1c, cost, and
A is incorrect because β-blockers are not associated potential for weight loss.
with an increased risk of the condition. Given the pa-
tient’s normal pituitary and thyroid tests, it is unlikely 9. Answer: D
that Answer B, prolactin-secreting adenoma, is correct. The usual course of therapy for a patient no longer able
Answer C is incorrect because pregnancy is not associ- to maintain adequate glycemic control with monother-
ated with an increased risk of the condition. apy is to add additional agents. Answer A is incorrect
because the patient is already exercising and still has
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uncontrolled hyperglycemia. Answer B is incorrect be- perglycemia despite basal/bolus insulin therapy. This
cause one agent would not normally be changed to an- patient is currently receiving a TDI dose of 24 units.
other unless a patient was experiencing adverse effects Dividing 1800 by the daily insulin dose provides an
of the original agent. In addition, GLP-1 analogs and estimate of the milligram per deciliter decrease one
DPP-4 inhibitors should not be used in patients with a would expect with the injection of 1 unit of a rapid-
history of pancreatitis; thus, both Answer B and An- acting insulin. For this patient, increasing 1 unit of in-
swer C are incorrect. sulin would be expected to decrease BG by 75 mg/dL
(1800/24 = 75). Answer A, Answer B, and Answer D all
10. Answer: C give alternative estimates.
Because monotherapy could achieve the A1c goal, a
sulfonylurea is a viable option, and with existing renal
impairment, glipizide is the most suitable choice. An-
swer A and Answer B are inappropriate choices for this
patient because the patient’s renal function is poor and
because he has class III heart failure, precluding the use
of metformin and pioglitazone, respectively. Although
no specific contraindications exist for this patient to use
sitagliptin, this agent as monotherapy is unlikely to get
this patient to his glycemic target of an A1c less than 7%.
11. Answer: C
This patient is experiencing sustained increases in fast-
ing glucose concentrations in the morning. The insulin
most likely to affect the morning glucose concentra-
tions is insulin glargine. Answer A and Answer B are
incorrect because the insulin lispro dose at dinnertime
will not likely affect the next morning’s glucose con-
centrations on the basis of the information provided in
the case. Answer D is incorrect on the basis of infor-
mation provided because it would more than likely in-
crease the next morning’s glucose concentrations, not
reduce them.
12. Answer: D
This patient weighs 50 kg (110 lb). 0.4 unit/kg/day x 50
kg = 20 units of TDI. When using insulin analogs, 50%
of the TDI dose should be used as an initial estimate of
the patient’s basal insulin needs; hence, 10 units will
be required. Glargine is a once-daily long-acting basal
insulin. Answer A and Answer B, although they use a
basal insulin, are incorrect because of the higher than
estimated dosage. Answer C is incorrect because insu-
lin aspart is used for bolus insulin doing, not for basal
therapy, unless the patient is using an insulin pump.
13. Answer: C
Correctional insulin dosing is necessary to optimize
glycemic control when the patient experiences hy-
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this case) would not likely help her bedtime BG and, swer C is incorrect because there is no need to obtain
because her fasting BG readings have been well con- another A1c this soon after the one 1 month ago, and
trolled, could lead to hypoglycemia (Answer C and An- the A1c according to ADA 2010 guidelines can be used
swer D). in the diagnosis of diabetes. Obtaining another glucose
reading on another day (Answer D) is also incorrect,,
9. Answer: A again because there are two abnormal glycemic indica-
This patient has relatively mild symptoms, and her tors already, so another is not necessary to confirm the
ablative therapy worked initially but now no longer diagnosis.
controls her thyroid levels. Methimazole would be the
oral agent of preference given its dosing frequency and 13. Answer: C
its lower risk of hepatotoxicity than PTU (Answer C). The LDL-C goal is less than 100 mg/dL. Statin therapy
Thyroidectomy is an option, but it is likely too aggres- is recommended, regardless of baseline LDL-C, for
sive for mild Graves disease; thus, Answer B is incor- patients with diabetes, and this patient’s LDL-C is el-
rect. Answer D is not optimal, and although β-blockers evated. In this case, the patient’s glycemic and blood
may provide symptomatic relief, they will not have a pressure readings are at their goals, less than 7.0% and
significant effect on her thyroid levels. less than 130/80 mm Hg, respectively, so adding insu-
lin (Answer A) and adding a blood pressure medication
10. Answer: D (Answer B) are not necessary. Answer D is incorrect
This patient has good control of his fasting glucose but because there is no need for fibrate therapy in this pa-
is experiencing postprandial hyperglycemia. An agent tient; the HDL-C and TG are under control.
that targets postprandial glucose, such as a DPP-4 in-
hibitor, would be most appropriate. Answer A is incor-
rect because this would exceed the maximal daily dose
for metformin. Answer B is incorrect because insulin
glargine is a basal insulin and has an effect on FPG but
little effect on postprandial glucose. Answer C is incor-
rect, again because it is a basal insulin and also because
it is more appropriate to add medications rather than
switch to another agent unless the patient is experienc-
ing adverse effects with the first agent.
11. Answer: D
She has tried dieting and some exercise, but these are
failing to control her weight; hence, her current routine
alone is not appropriate, making Answer A incorrect.
Answer B and Answer C are both federally scheduled
medications because of their abuse potential. Given her
history, these are not appropriate choices. Orlistat may
provide some weight loss in addition to improvements
in her diet and physical activity.
12. Answer: A
This patient has now had two laboratory glycemic in-
dicators consistent with the diagnosis of diabetes. An-
swer B is not likely correct because this patient has
several risk factors for the development of type 2 DM
including obesity, ethnicity, age, a history of gestational
diabetes, and a strong family history of the disease. An-
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