Endocrine and Metabolic Disorders PDF

Endocrine and Metabolic Disorders b. c. Discontinue causative agent if drug induced. i. Recheck prolactin concentration 3 days after discontinuation. ii. Select agent with similar action but no known effect on prolactin concentrations. iii. If discontinuation of causati...

Endocrine and Metabolic Disorders b. c. Discontinue causative agent if drug induced. i. Recheck prolactin concentration 3 days after discontinuation. ii. Select agent with similar action but no known effect on prolactin concentrations. iii. If discontinuation of causative agent not feasible, consider dopamine agonist Dopamine agonists (preferred to surgery in most cases) i. Cabergoline (preferred agent according to the Endocrine Society guidelines, long-acting oral agent; adverse effect profile similar to that for bromocriptine but fewer gastrointestinal [GI] adverse effects) (a) Initial: 0.5 mg once weekly (b) Maximal: 4.5 mg/week ii. Bromocriptine (see previous text) iii. Efficacy: May restore fertility in more than 90% of women. Long-term cure rates are around 60% for smaller tumors, around 25% for larger tumors. Cabergoline may be easier for patients to take, given its weekly administration. iv. Consider tapering or discontinuing after 2 years of therapy if asymptomatic, prolactin concentrations normalized, and no tumor remnant by imagery D. GH Deficiency: 1. Diagnosis and clinical presentation a. Decreased GH concentrations after provocative pharmacologic challenge (e.g., insulin, clonidine, GH-releasing hormone) b. Clinical presentation i. Delayed growth velocity or short stature ii. Central obesity iii. Immaturity of the face or prominence of the forehead 2. Therapy goals a. Increase growth velocity b. Increase final adult height when treating children 3. Therapeutics: Recombinant GH (somatropin) a. Dosing i. Depends on which of the various products are selected (dosed subcutaneously or intramuscularly once daily) ii. When to discontinue therapy on the basis of growth velocity is controversial. iii. Once- or twice-monthly long-acting depot formulation is also available. b. Adverse effects i. Arthralgia, injection-site pain ii. Rare but serious cases of idiopathic intracranial hypertension have been reported. c. Efficacy: All products are considered equally efficacious. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-214 Endocrine and Metabolic Disorders III. ADRENAL GLAND DISORDERS Mineralocorticoids (aldosterone) RAS + ve zona glomerulosa Medulla (catecholamines) zona reticularis Sex hormones (testosterone/ estradiol) zona fasciculata + ve – ve Pituitary ACTH Cortisol – ve Figure 2. Basic adrenal cortex hormone physiology. ACTH = adrenocorticotropic hormone; RAS = renin-angiotensin system; +ve = positive stimulation; –ve = negative feedback. Patient Case 4. A 44-year-old man has consistently high blood pressure (172/98 mm Hg today), despite his 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 plasma aldosterone/renin ratio is 125 (normal is less than 25). Which most likely caused this patient’s uncontrolled hypertension? A. Cushing syndrome. B. Addison disease. C. Hyperprolactinemia. D. Hyperaldosteronism. A. Hypersecretory Cortisol Diseases (Cushing syndrome) 1. Classification a. ACTH-dependent: Result of excessive ACTH secretion i. Pituitary corticotroph adenoma (Cushing disease) ii. Ectopic ACTH syndrome (extrapituitary tumor) b. ACTH-independent: Result of excessive cortisol secretion or exogenous steroids i. Unilateral adrenocortical tumors ii. Bilateral adrenal hyperplasia or dysplasia iii. Exogenous steroid administration ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-215 Endocrine and Metabolic Disorders 2. Diagnosis and clinical presentation a. Presence of hypercortisolism through 24-hour urinary free cortisol concentration b. Differentiate etiology (key to treatment options). i. Plasma ACTH concentrations (normal or elevated in ACTH-dependent) ii. Pituitary magnetic resonance imaging (Cushing syndrome vs. ectopic ACTH syndrome) iii. Overnight dexamethasone suppression test iv. Late-night salivary cortisol concentration v. 24-hour urinary free cortisol (low sensitivity) c. Clinical presentation i. Central obesity and facial rounding quite common ii. Peripheral obesity and fat accumulation iii. Myopathies iv. Osteoporosis, back pain, compression fracture v. Abnormal glucose tolerance or diabetes vi. Amenorrhea and hirsutism in women vii. Lower abdominal pigmented striae (red to purple) viii. Hypertension (principal cause of morbidity and mortality) 3. Therapy goals a. Reduce morbidity and mortality and eliminate cause b. Reverse clinical features c. Normalize biochemical changes (when possible) d. Achieve long-term control without recurrence (remission when possible) 4. Therapeutics a. If excessive exogenous corticosteroid use is causative, discontinue or minimize use. b. Surgical resection of causative area or tumor is usual treatment of choice. c. Pharmacotherapy is usually reserved on the basis of the same criteria listed earlier for pituitary adenomas. d. Efficacy is measured by control of symptoms and normalization of 24-hour urine-free cortisol concentrations. e. Glucocorticoid replacement may be necessary if circulating cortisol is reduced to lower than physiologic concentrations. f. Inhibit ACTH secretion i. Pasireotide (a) Mechanism of action: Somatostatin analog blocks ACTH secretion from pituitary, leading to decreased circulating cortisol concentrations (better selectivity to pertinent somatostatin receptors than other analogs such as octreotide). Usually not effective for adrenally caused Cushing syndrome. (b) Dosing: 0.6–0.9 mg twice-daily subcutaneous injection (dose adjustments based on urinary free cortisol and symptom improvements). Also available in a once-monthly intramuscular formulation. (c) Adverse effects: Hyperglycemia, hypocorticalism, diarrhea, nausea, gallstones, headache, bradycardia (d) Obtain an electrocardiogram, FPG, A1C, liver function tests, and gallbladder ultrasonography before initiating therapy. (e) Self-monitor BG values every week for first 2–3 months, and then periodically obtain liver function tests 1–2 weeks after starting therapy; then obtain them monthly for 2–3 months and then every 6 months. Repeat gallbladder ultrasonography at 6- to 12-month intervals. ii. Cabergoline (see dosing and ADR profile listed earlier) ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-216 Endocrine and Metabolic Disorders g. Inhibit cortisol synthesis i. Osilodrostat (a) Mechanism of action: Hinders cortisol production by blocking the 11-β-hydroxylase enzyme (b) Dosing (1) Initial: 2 mg twice daily by mouth (2) Maximal: 30 mg twice daily (c) Adverse effects (1) Headache (2) Nausea/vomiting (3) Fatigue (4) QT prolongation (obtain baseline electrocardiogram 1 week after initiating therapy) ii. Ketoconazole (a) Mechanism of action: In addition to its antifungal activity, it hinders cortisol production by inhibiting 11β- and 17α-hydroxylase. (b) Dosing (1) Initial: 200 mg twice daily by mouth (2) Maximal: 400 mg three times daily (c) Adverse effects (1) Gynecomastia (2) Abdominal discomfort (3) Reversible hepatic transaminase elevations (4) Be aware of potential drug-drug interactions; inhibits CYP3A4 (strong), P-glycoprotein/ ABCB1. iii. Mitotane (a) Mechanism of action: Inhibits 11β-hydroxylase but also has some direct adrenolytic activity (b) Dosing (1) Initial: 500–1000 mg/day by mouth (some use much higher daily dosages, but they are not well tolerated) (2) Maximal: 9–12 g/day (c) Adverse effects (1) Adrenocortical atrophy: Can persist on discontinuation and, in severe cases, may necessitate androgen and glucocorticoid replacement (2) Anorexia (3) Ataxia (4) Abdominal discomfort (5) Lethargy iv. Etomidate (a) Mechanism of action: Similar to ketoconazole, inhibits 11β-hydroxylase (b) Dosing (1) Initial: 0.03 mg/kg intravenously, followed by a 0.1-mg/kg/hour infusion (2) Maximal: 0.3 mg/kg/hour (c) Adverse effects (1) Pain at injection site (2) Nausea and vomiting (3) Myoclonus (4) Psychoses (d) Given route of administration is usually reserved for when rapid control of cortisol concentrations is needed and oral therapy is problematic. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-217 Endocrine and Metabolic Disorders v. Metyrapone (by compassionate use only) (a) Mechanism of action: Hinders secretion of cortisol by blocking final step in cortisol synthesis by inhibiting 11β-hydroxylase activity (b) Dosing (1) Initial: 500 mg three times daily by mouth (2) Average dose in Cushing syndrome is 2000 mg/day, but dose is about 4000 mg in ectopic ACTH syndrome. (c) Adverse effects (1) Hypoadrenalism (2) Hypertension (3) Worsening of hirsutism and acne if present before treatment (4) Headache (5) Abdominal discomfort h. Mifepristone for hyperglycemia associated with endogenous Cushing syndrome; proposed to limit binding of cortisol; can reduce insulin requirements and improve clinical symptoms associated with hyperglycemia B. Hyperaldosteronism: Primary Aldosteronism 1. Classification a. Bilateral adrenal hyperplasia (70% of cases) b. Aldosterone-producing adenoma (30% of cases) 2. Diagnosis and clinical presentation a. Elevated plasma aldosterone/renin ratio (normal ratio is less than 25) b. Other features: Hypernatremia, hypokalemia, hypomagnesemia, glucose intolerance c. Clinical presentation (can be asymptomatic) i. Hypertension ii. Muscle weakness or fatigue iii. Headache iv. Polydipsia v. Nocturnal polyuria 3. Therapy goals (same as earlier for Cushing syndrome) 4. Therapeutics a. Spironolactone (drug of choice) i. Mechanism of action: mineralocorticoid receptor antagonist 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. C. Hyposecretory Adrenal Disorders 1. Classification a. Primary adrenal insufficiency (i.e., Addison disease) i. Caused by autoimmune disorder, infection, or infarction ii. Results in cortisol, aldosterone, and androgen deficiencies ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-218 Endocrine and Metabolic Disorders b. Secondary adrenal insufficiency i.  Exogenous steroid use (from chronic suppression); oral, inhaled, intranasal, and topical administration ii. Surgery, trauma, infection, infarction iii. Results in impaired androgen and cortisol production 2. Diagnosis and clinical presentation (focus on Addison disease) 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 blood urea nitrogen 3. Therapy goals (same as earlier for Cushing syndrome) 4. Therapeutics (Table 2) 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 or variable serum concentrations in some patients. (b) Daily cortisol production in average patient: 5–10 mg/m2 b. Hydrocortisone: 15 mg/day (use may reduce need for fludrocortisone compared with use of 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 d. For women with decreased libido or low energy levels because of androgen deficiency, dehydroepiandrosterone: 25–50 mg/day e. Efficacy can be measured by symptom improvement. f. Note that during times of stress or illness, corticosteroid dosages must be increased. Dose and route of administration depend on level of stress to the body. Table 2. Comparative Glucocorticoid Dosing Glucocorticosteroid Cortisone Hydrocortisone Prednisone Prednisolone Triamcinolone Methylprednisolone Dexamethasone Relative Equivalent Dosing (mg) 25 20 5 5 4 4 0.75 ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-219 Endocrine and Metabolic Disorders IV. OBESITY A. Guidelines 1. American College of Cardiology/American Heart Association (ACC/AHA) and The Obesity Society 2013 guidelines. Most of the therapeutic agents that follow were approved for obesity after the guideline was initiated and are not included. 2. Endocrine Society 2015 guidelines are focused on new obesity agents. No specific recommendations of a particular agent over another, but a good review of the therapeutic options 3. AACE/American College of Endocrinology 2016 guidelines. A comprehensive review of nonpharmacologic and pharmacologic therapy for obesity. Like the Endocrine Society guidelines, there are no specific recommendations regarding one agent over another. B. Classification 1. Based on BMI 2. Normal: BMI 18.5–24.9 kg/m2 3. Overweight: BMI 25.0–29.9 kg/m2 4. Obesity a. Class I: BMI 30.0–34.9 kg/m2 b. Class II: BMI 35.0–39.9 kg/m2 c. Class III: BMI 40 kg/m2 or greater C. Therapy Goals 1. Weight loss: Initial goal: 5%–10% decrease from baseline weight over 6 months 2. Maintain lower weight in the long term 3. Limit weight-induced comorbidities (e.g., T2D, hypertension, cardiovascular disease) D. Nonpharmacologic Therapy (aimed at providing an energy deficit) 1. Increased physical activity: 200–300 minutes per week (minimum 150) 2. Dietary options: Any diet that has proven weight reduction data available is appropriate. No specific recommendations of one diet over another. Individualize according to patient preferences. a. Strive for at least a 500-kcal/day deficit. b. 1200–1500 kcal/day for women c. 1500–1800 kcal/day for men 3. Behavioral intervention: According to ACC/AHA/The Obesity Society guidelines: Preferably in-person, high-intensity (at least 14 sessions in 6 months) comprehensive weight-loss intervention through group or individual sessions with a professional (e.g., dietitian, exercise specialist, health counselor) 4. Surgery: Usually reserved for patients with class III obesity (BMI greater than 40 kg/m 2) or BMI of at least 35 kg/m2 with at least one obesity-related comorbidity such as diabetes, hypertension, or obstructive sleep apnea a. Roux-en-Y gastric bypass (decreasing in frequency) b. Sleeve gastrectomy (now the most common surgery) c. Adjustable gastric banding 5. Gastric balloons and transpyloric shuttle available for weight loss, Plenity (cellulose/citric acid) available for weight management ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-220 Endocrine and Metabolic Disorders Patient Case 5. A patient takes the maximal daily dose of phentermine/topiramate for the treatment of obesity. The patient’s baseline BMI is 36 kg/m2 and weight is 115.7 kg (255 lb). Which best represents the minimum weight loss required to consider continuing treatment with this agent after 3 months of therapy? A. 3.2 kg (7 lb). B. 5.9 kg (13 lb). C. 7.7 kg (17 lb). D. 11.8 kg (26 lb). E. Pharmacotherapy 1. Always in conjunction with diet, physical activity, and behavioral therapy 2. Medications should be reserved for those not achieving or sustaining weight reduction with adequate lifestyle modifications, in those with obesity, or in those with a BMI of at least 27 kg/m 2 with significant weight-related comorbidities (e.g., diabetes, hypertension, dyslipidemia). 3. Medication selected according to risk-benefit profile should be approved by the U.S. Food and Drug Administration (FDA). After 1 year, approved agents should provide at least a statistically significant 5% weight loss difference from placebo, or at least 35% of treated subjects should achieve at least a 5% weight loss from baseline and twice that of placebo-treated subjects. 4. Orlistat a. Mechanism of action: Reduced absorption of fat by inhibition of gastric and pancreatic lipases b. Dosing i. Prescription: 120 mg three times daily during or up to 1 hour after meals ii. Over the counter: 60 mg three times daily during or up to 1 hour after meals c. Adverse effects i. GI tract: Flatulence, oily stools, loose stools, fecal urgency, or incontinence (highly 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, kidney stones (FDA warnings) 5. Phentermine/extended-release topiramate (schedule IV) a. Mechanism of action: Phentermine promotes appetite suppression and decreases food intake secondary to its sympathomimetic activity. Mechanism of topiramate is unknown, but it can cause appetite suppression and satiety through increased γ-aminobutyrate activity. b. Dosing (phentermine/topiramate): Should be taken in the morning to avoid insomnia i. Initial: 3.75/23 mg daily for 2 weeks; then increase to 7.5/46 mg daily ii. If at least a 3% weight loss not achieved after 12 weeks, can discontinue or increase to 11.25/ 69 mg daily for 2 weeks; then increase to 15/92 mg daily, if tolerated iii. If at least a 5% weight loss not achieved with 15/92 mg daily, discontinue use. Taper when discontinuing to avoid seizures. iv. Dosing in moderate hepatic or renal impairment: Do not exceed 7.5/46 mg daily. c. Adverse effects: Dry mouth, paresthesia, constipation, dysgeusia, insomnia, attention and memory disturbances, increased heart rate d. In women of childbearing age, obtain a negative pregnancy test before initiating and monthly thereafter because of fetal toxicity. Stress the importance of adequate contraception during use. e. Discontinue use if patient does not achieve at least a 5% weight loss after 12 weeks of use. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-221 Endocrine and Metabolic Disorders 6. Bupropion/naltrexone a. Mechanism of action: Reuptake inhibitor of dopamine and norepinephrine (bupropion) and opioid antagonist (naltrexone) b. Dosing (8 mg naltrexone/90 mg bupropion tablets extended release) i. Dosage escalation at weekly intervals by 1 tablet daily ii. Initially, 1 tablet once daily iii. Target dosage: 2 tablets twice daily c. Adverse effects: Nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth d. Precautions and contraindications: Uncontrolled hypertension, seizure disorders, anorexia nervosa or bulimia, drug or alcohol withdrawal. Avoid with chronic use of opioids. e. Discontinue use if at least a 5% weight loss is not achieved after 12 weeks of use. 7. Liraglutide a. Mechanism of action: Glucagon-like peptide-1 (GLP-1) agonist (part of incretin system). Thought to cause satiety and delay gastric emptying. Used in treatment of T2D (see text that follows) b. Dosing (administered subcutaneously by pen device) i. Target dosage higher in obesity than in treatment of diabetes. Brand-name product for obesity is not approved for diabetes and vice versa. ii. Initially, 0.6 mg once daily; increase by 0.6 mg at weekly intervals iii. Target dosage for obesity: 3 mg daily c. Adverse effects: Nausea, vomiting, diarrhea, constipation, dyspepsia d. Precautions and contraindications i. See the Diabetes Mellitus section. ii. Do not use with other GLP-1 agonists used in the treatment of diabetes mellitus (DM). e. Discontinue use if the patient does not achieve at least a 4% weight loss after 16 weeks of therapy or if the patient cannot tolerate the target 3-mg daily dosage. 8. Semaglutide a. Mechanism of action similar to liraglutide b. Dosing (administered subcutaneously by pen device) i. Target dose, like liraglutide, is higher than in the treatment of diabetes and the brand name is also different. ii. Initially, 0.25 mg once weekly, increased at monthly intervals iii. Target dose for obesity: 2.4 mg once weekly c. Adverse effects, precautions, contraindications: Similar to liraglutide d. Discontinue if patient cannot tolerate the target dose. 9. Tirzepatide does not yet have FDA approval for weight loss but seems likely based on recent data published in the New England Journal of Medicine. 10. Diethylpropion (schedule IV), phentermine (schedule IV), phendimetrazine (schedule III) a. Should be used only for a limited time, up to 3 months, and avoid in those with abuse potential b. Clinical guidelines do not recommend their use. c. Adverse effects: Increased blood pressure, constipation, increased heart rate, dysrhythmias, abuse potential (avoid in patients with hypertension or a history of cardiovascular disease) 11. Other issues a. Concurrent use of obesity medications has not been studied. b. Comparative studies between agents are lacking (although liraglutide appears more effective at weight loss compared to orlistat, and semaglutide is more effective compared to liraglutide). c. Long-term safety of all agents is unknown. d. Consider obesity a chronic condition. Weight gain after discontinuation of agent is likely 12. Off-label medications used but not well studied specifically for obesity: Selective serotonin reuptake inhibitors, zonisamide, metformin, pramlintide 13. Lorcaserin was removed from the market in early 2020 after increased risk of some cancers was detected. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-222 Endocrine and Metabolic Disorders V. POLYCYSTIC OVARY SYNDROME A. Background and Classification 1. Can be a cause of infertility in up to 20% of infertile couples 2. Mainly considered to be caused by androgen excess or hyperandrogenism 3. Underlying cause appears to be insulin resistance (in patients with and without obesity), with subsequent compensatory insulin hypersecretion or increased insulin action. This increased action stimulates androgen secretion by the ovaries or adrenal cells, leading to increased luteinizing hormone (LH) secretion but normal or low follicle-stimulating hormone (FSH) concentrations, with a subsequent decrease in follicular maturation and anovulation. 4. Has several potential comorbidities with endocrine and cardiovascular implications (e.g., T2D, obesity) 5. Can affect 6%–10% of women (or more depending on diagnostic criteria used), making it one of the most prevalent endocrine disorders in young women 6. Women younger than 50 are at higher cardiovascular disease risk. B. Diagnosis 1. Still somewhat under debate; no clear consensus 2. 1990 National Institutes of Health criteria a. Hyperandrogenism or hyperandrogenemia b. Oligo-ovulation (infrequent or irregular ovulation) c.  Exclusion of other secondary causes, particularly adrenal hyperplasia, Cushing syndrome, hyperprolactinemia 3. 2003 Rotterdam criteria: Presence of at least two of the following and ruling out secondary causes a. Menstrual irregularity (oligo-ovulation or anovulation) b. Hyperandrogenism (clinical or biochemical signs) c. Polycystic ovaries (by transvaginal ultrasonography) d. Recommended by the Endocrine Society guideline 4. 2006 Androgen Excess Society: Follow 1990 National Institutes of Health 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 the sole criterion because 20%–40% of patients with PCOS may be in the normal range) a. Elevated free or total serum testosterone b. 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 patients with obesity (50%–80% of cases), prediabetes (impaired glucose tolerance) or T2D may be present. D. Therapy Goals 1. Normalize ovulation and menses 2. Improve fertility in those who want to become pregnant 3. Limit clinical signs 4. Reduce progression to T2D (perhaps cardiovascular disease) ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-223 Endocrine and Metabolic Disorders E. Nonpharmacologic Therapy 1. Weight loss (5%–10%) important in patients who are overweight or have obesity 2. Mechanical hair removal for hirsutism F. Pharmacotherapy 1. Fertility improvement 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 dosage: 150–200 mg/day iii. Adverse effects: Flushing, GI discomfort, vision disturbances, vaginal dryness, multiple pregnancies iv. Improved ovulation and pregnancy rates when used in combination with metformin b. Gonadotropin (e.g., recombinant FSH) or recombinant gonadotropin-releasing hormone therapy with or without clomiphene i. Mechanism of action: Normalizes LH/FSH ratio to stimulate ovulation ii. Dosing: Many dosing strategies used iii. Adverse effects: Multiple pregnancies, ovarian hypertrophy, miscarriage, mood swings, breast discomfort c. Letrozole i. Mechanism of action: Aromatase inhibitor prevents conversion of androgens to estrogen, which results in an increased secretion of FSH from the anterior pituitary; conflicting meta-analysis data on its effectiveness compared with clomiphene on pregnancy rates ii. Dosing: 2.5–5 mg daily iii. Adverse effects: Edema, sweating, constipation, nausea, arthralgias, headache iv. Considered the treatment of choice for ovulation induction by the American College of Obstetricians and Gynecologists in 2018 because of better live birth rates than with clomiphene 2. Symptomatic improvement a. Hormonal contraceptives (estrogen/progestin combination): Endocrine Society first-line therapy for menstrual abnormalities, hirsutism, or acne b. Metformin i. Effective for metabolic and glycemic abnormalities, if present, but only modestly effective for hirsutism ii. Alternative to hormonal contraception for irregular menses when hormonal contraceptives are contraindicated iii. Few data to support use for increased fertility (may improve pregnancy rate but not shown to improve rates of live births) c. Spironolactone i. Often added to hormonal contraceptives ii. Can help with hirsutism d. Pioglitazone: Questionable whether benefits outweigh risks in PCOS. Not recommended in Endocrine Society guidelines ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-224 Endocrine and Metabolic Disorders VI. DIABETES MELLITUS 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/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. T1D a. Attributable to cellular-mediated β-cell destruction leading to insulin deficiency (insulin needed for survival) b. Accounts for 5%–10% of DM c. Formerly known as insulin-dependent diabetes and juvenile-onset diabetes d. Usually presents in childhood or early adulthood but can present in any stage of life e. Usually symptomatic with a rapid onset in childhood, but a slower onset can occur in older adults f. The ADA now recommends a staging of patients with T1D based on the degree of dysglycemia and symptoms. i. Stage 1: Multiple autoantibodies present but glucose concentrations are normal ii. Stage 2: Multiple autoantibodies present, glucose concentrations consistent with prediabetes (see criteria in text that follows), and patient is asymptomatic iii. Stage 3: Symptomatic and glucose concentrations consistent with diabetes (see criteria in text that follows) 2. T2D a. Results primarily from insulin resistance in muscle and liver, with subsequent defect in pancreatic insulin secretion, though GI, brain, liver, and kidneys are all involved in the pathophysiology b. Accounts for 90%–95% of diabetes mellitus c. Formerly known as non–insulin-dependent diabetes or adult-onset diabetes d. Often asymptomatic, with a slow onset over 5–10 years. Rationale for early, frequent screening of those at risk (see text that follows) and initial assessment for complications at diagnosis e. Increased trends in T2D in children and adolescents attributed to rise in obesity 3. Maturity-onset diabetes of the young 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 can mimic T1D or T2D c. Often misdiagnosed for type 1 diabetes. Patients may respond to sulfonylurea therapy. 4. Gestational diabetes a. Glucose intolerance occurring during pregnancy b. Prevalence: 1%–14% of pregnancies (complicates about 4% of pregnancies) c. Most common in third trimester 5. Prediabetes a. Impaired glucose tolerance b. Impaired fasting glucose 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) ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-225 Endocrine and Metabolic Disorders Patient Case 6. A 64-year-old African American woman has had a 12-kg (27 lb) weight increase during the past year, primarily because of inactivity and a poor diet. Her BMI is 44 kg/m2. Her mother and sister both have T2D. Her fasting glucose concentration today is 212 mg/dL. Which is the best course of action? A. Diagnose T2D and begin treatment. B. Diagnose T1D and begin treatment. C. Obtain another glucose concentration today. D. Obtain an A1C today in addition to the glucose concentration. C. Screening for DM (using glycemic diagnostic criteria discussed in greater detail in the text that follows) 1. T1D a. Symptomatic patients b. Asymptomatic patients at higher risk i. First-degree relatives with T1D ii. Measure islet autoantibodies to assess risk of T1D. iii. If screen is positive for antibodies, counsel on symptoms of hyperglycemia and risk of DM. Consider enrollment in observational study. 2. T2D a. Age 35 or older, repeat every 3 years if normal b. Screen regardless of age if BMI is 25 kg/m2 or greater (23 kg/m2 or greater in Asian Americans) and at least one of the following risk factors: i. History of cardiovascular disease ii. A1C is 5.7% or greater, impaired glucose tolerance, or impaired fasting glucose in previous testing iii. History of PCOS iv. HDL less than 35 mg/dL or TG greater than 250 mg/dL v. Hypertension vi. High-risk ethnicity: African American, Latino, Native American, Asian American, Pacific Islander vii. First-degree relative with T2D viii. Physical inactivity ix. Insulin resistance conditions (e.g., severe obesity, acanthosis nigricans) 3. Gestational DM a. Screen at first prenatal visit for undiagnosed T2D in all patients with T2D risk factors present. b. Screen at 24–28 weeks’ gestation using OGTT. c. If a diagnosis of gestational DM is made, screen for diabetes 4–12 weeks after delivery. d. Continue to screen patients who have had gestational DM every 3 years for T2D for life. D. DM Diagnosis 1. T1D and T2D diagnosis a. Glycemic values in nonpregnant patients i. FPG (a) Easy, convenient (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. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-226 Endocrine and Metabolic Disorders iii. OGTT (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. A1C (glycated hemoglobin) (a) 6.5% or greater (b) May be less sensitive than FPG in identifying mild diabetes, but does not require fasting and has less variability from day to day (c) A1C values may be inaccurate in patients with anemia, chronic malaria, sickle cell anemia, pregnancy, or significant blood loss or recent blood transfusion. v. Unless a clinical diagnosis is clear, including symptoms of hyperglycemia, diagnosis requires two abnormal tests showing hyperglycemia and can be obtained from the same sample (using two of the above criteria) or in two separate test samples (can be the same type of test). b. Other useful diagnostic tests if type of DM is in question i. C-peptide (measure of endogenous insulin secretion, usually negligible in T1D and normal or elevated early in T2D) ii. Presence of islet cell autoantibodies, autoantibodies to insulin, glutamic acid decarboxylase, or tyrosine phosphatase (all suggest autoimmune activity) 2. Gestational diabetes diagnosis: Glycemic values in pregnancy a. Updated and simplified diagnostic criteria b. “One-step” approach: 75-g OGTT at 24–28 weeks’ gestation i. Fasting: 92 mg/dL or greater ii. 1 hour after OGTT: 180 mg/dL or greater iii. 2 hours after OGTT: 153 mg/dL or greater c. “Two-step” approach: 50-g OGTT (nonfasting) at 24–28 weeks’ gestation i. If 1 hour after 50-g OGTT is less than 140 mg/dL, no further workup ii. If 140 mg/dL or greater, do additional fasting OGTT using 100 g (see the ADA guidelines for diagnostic glucose criteria) 3. Prediabetes diagnosis (high-risk population) a. Impaired fasting glucose: FPG 100–125 mg/dL b. Impaired glucose tolerance: 2-hour plasma glucose after OGTT (75 g) of 140–199 mg/dL c. A1C 5.7%–6.4% d. Screen yearly for T2D if positive for prediabetes Patient Case 7. A 56-year-old man with T2D takes metformin 1000 mg twice daily. He has no other chronic diseases or history of cardiovascular disease. His current vital signs and laboratory results are as follows: blood pressure 148/78 mm Hg, heart rate 74 beats/minute, and A1C 6.9%. Which agent, if added to the current regimen, has the most potential to reduce both microvascular and macrovascular complications in this patient? A. Insulin glargine. B. Lisinopril. C. Glyburide. D. Niacin. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-227 Endocrine and Metabolic Disorders E. Goals of Diabetes Management in Nonpregnant Adults 1. Primary goal: Prevent the onset of acute or chronic complications 2. Acute complications: Hypoglycemia, diabetic ketoacidosis (DKA), hyperglycemic hyperosmolar nonketotic syndrome 3. Chronic complications a. Microvascular: Retinopathy, nephropathy, and neuropathy b. Macrovascular: Cardiovascular, cerebrovascular, and peripheral vascular diseases 4. Glycemic therapy goals a. A1C less than 7.0% (Note: The American College of Endocrinology/AACE guidelines recommend 6.5% or less.) i. Obtain every 6 months in patients at goal A1C and every 3 months in those over goal. ii. Less-stringent A1C targets may be appropriate in those with a short life expectancy (e.g., terminal cancer), advanced diabetic complications, longstanding diabetes that is difficult to control (e.g., frail older adults with a history of hypoglycemia at risk of falls), or extensive other comorbidities (clinical atherosclerotic cardiovascular disease). (In such situations, a higher A1C [e.g., less than 8%] may be sufficient to limit the risk of acute complications of hyperglycemia such as dehydration and electrolyte deficiencies while preventing exacerbation of comorbidities.) b. FPG or premeal 80–130 mg/dL. Frequency of monitoring depends on regimen, type of DM, and current glycemic control. c. Peak postprandial glucose (1–2 hours after a meal) less than 180 mg/dL d. Time in glycemic range 70% or greater and time below range less than 4% (for patients with continuous glucose monitoring systems) 5. Non-glycemic therapy goals a. Blood pressure i. The ADA recommends a blood pressure goal of less than 130/80 mm Hg in patients at high risk of cardiovascular disease (existing cardiovascular disease or greater than a 15% ten-year risk) and a goal of less than 140/90 mm Hg in those at lower risk. ii. ACC/AHA hypertension guidelines recommend less than 130/80 mm Hg. b. Lipids i. ADA: No specific LDL goal is currently recommended. ii. ACC/AHA 2018 guidelines suggest lowering LDL by 30%–49% in patients with diabetes age 40–75 and by at least 50% if at higher risk, e.g. age 50-75 or patient has other risk factors. iii. No specific TG or HDL goals are currently recommended. F. Goals for Gestational Diabetes 1. Primary goal: Prevent complications to mother and child. 2. Glycemic therapy goals (more stringent) a. FPG of 95 mg/dL or less b. 1-hour postprandial glucose 140 mg/dL or less c. 2-hour postprandial glucose 120 mg/dL or less 3. Potential complications of hyperglycemia during pregnancy a. Mother: Hypertension, preeclampsia, T2D after pregnancy b. Fetus/child: Macrosomia, hypoglycemia, jaundice, respiratory distress syndrome ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-228 Endocrine and Metabolic Disorders G. Benefits of Optimizing Diabetes Management in Nonpregnant Adults 1. Glycemic control a. Reduces the risk of developing retinopathy, nephropathy, and neuropathy in T1D and T2D b. Prospective studies, specifically designed to assess optimizing glycemic control and effect on cardiovascular events, have shown little or no reduction in cardiovascular outcomes. c. However, the “legacy” effect (also known as “metabolic memory”) in the Diabetes Control and Complications Trial of T1D and the UK Prospective Diabetes Study of T2D suggests early control has future cardiovascular benefit. d. No profound benefit of aggressive glycemic control in T2D (A1C less than 6.5%) 2. Blood pressure control: Reduction in both macrovascular and microvascular complications 3.  Lipid control: Reduction in LDL with moderate-intensity statin therapy reduces cardiovascular complications. Patient Case 8. A 21-year-old patient (weight 80 kg) is given a diagnosis of T1D after the discovery of elevated glucose concentrations (average 326 mg/dL), and the patient has signs and symptoms of hyperglycemia. Which is the most appropriate initial dose of rapid-acting insulin before breakfast for this patient? (Assume a TDI regimen of 0.5 unit/kg/day.) A. 2 units. B. 4 units. C. 7 units. D. 14 units. H. Therapeutic Management of T1D (Table 3) 1. Insulin agents a. Categorized on the basis of duration after injection i. Rapid acting: Insulin aspart (two formulations), lispro, (two formulations) glulisine, and inhaled insulin ii. Short acting: Regular human insulin iii. Intermediate acting: Neutral protamine Hagedorn (NPH) iv. Long acting: Insulin glargine, degludec and detemir b. Combination insulin products (intermediate or long acting, regular or rapid acting): 70/30, 75/25, insulin degludec and glargine available in combination with GLP-1 agonist c. Higher-concentration insulin products i. More commonly used in patients with T2D needing significant daily insulin doses ii. U-300 glargine (300 units/mL), U-200 degludec (200 units/mL), U-200 lispro (200 units/mL), U-500 regular insulin (500 units/mL) ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-229