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Endocrine and Metabolic Disorders Table 3. Characteristics of U-100 (100 units/mL) Insulinsa Category Drug Name Clarity Onset Administration Time Before Meal (min) Peak (hr) Duration (hr) Rapid acting Aspart Lispro Glulisine Inhaled insulin Clear 15–30 min 15 (shorter with fast-acting a...

Endocrine and Metabolic Disorders Table 3. Characteristics of U-100 (100 units/mL) Insulinsa Category Drug Name Clarity Onset Administration Time Before Meal (min) Peak (hr) Duration (hr) Rapid acting Aspart Lispro Glulisine Inhaled insulin Clear 15–30 min 15 (shorter with fast-acting aspart/lispro) (inhaled insulin at beginning of meal) 1–3 (shorter with inhaled and fast-acting aspart/lispro) 2–5 (shorter with inhaled and fast-acting aspart/lispro) Short acting Regular Clear 30–60 min 30 2–3 4–6 Intermediate acting Neutral protamine Hagedorn Cloudy 1–2 hr N/A 4–8 10–20 Long acting Detemir Glargine Degludec Clear 2–4 hr 1–2 hr 1–2 hr N/A 6–8 “Peakless” “Peakless” 6–24 ~24 24–42 The times given depend on the source of data and intersubject variability. N/A = not applicable. a d. Glycemic target i. Regular- and short-acting insulins target postprandial glucose concentrations. ii. Intermediate- and long-acting insulins target fasting glucose concentrations. e. Inhaled insulin may cause bronchospasm and is contraindicated in patients with asthma, chronic obstructive pulmonary disease, or lung cancer. Requires spirometry testing at baseline, at 6 months of therapy, and annually thereafter 2. Management of insulin therapy a. First step is to estimate TDI requirements. b. Weight-based estimate if insulin naive i. 0.3–0.6 unit/kg/day ii. Requirements higher if treating DKA near initial diagnosis of DM iii. Honeymoon phase shortly after treatment initiation often requires lower daily insulin needs. c. With older insulin formulations (NPH and regular insulin) i. Two-thirds of TDI is given before the morning meal. Two-thirds of this is given as NPH, and one-third is given as regular insulin. ii. One-third of TDI is given before the evening meal. Either with two-thirds given as NPH and one-third given as regular insulin or in a 1:1 ratio. Alternative is regular given before evening meal and NPH at bedtime. iii. Advantages: Daily insulin injection frequency two or three times daily and less expensive than newer insulins iv. Disadvantages: Does not mimic natural insulin secretion pattern; prone to hypoglycemic events d. Basal-bolus insulin therapy (i.e., physiologic insulin therapy) i. Use insulin analogs to better mimic natural insulin secretion patterns ii. Use long-acting basal insulin to prevent ketosis and control FPG iii. Use bolus insulin to control postprandial hyperglycemia iv. Basal insulins: Insulin glargine or degludec once daily or insulin detemir once or twice daily v. Bolus insulins: Rapid-acting insulin (can use short-acting insulin) vi. Basal requirements are typically 50% of estimated TDI, but some practitioners may prefer more or less. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-230 Endocrine and Metabolic Disorders vii. Bolus requirements are typically 50% of estimated TDI split three ways before meals. (a) Provides initial estimate of prandial insulin needs (b) Typically, patients begin to estimate bolus requirements given the amount of carbohydrates to be ingested. Requires significant patient education in food carbohydrate estimates (c) Alternative bolus requirement (Rule of 500): Dividing 500 by TDI will estimate the amount of carbohydrates (in grams) that 1 unit of a rapid-acting insulin will cover. viii. Advantages over NPH plus regular approach: More physiologic, less hypoglycemia, more flexible to patient mealtimes ix. Disadvantages: Cost and increased frequency and number of daily injections (rapid-acting and basal insulin must be injected separately). Note that the same process of basal-bolus insulin therapy can apply to a patient with T2D who is receiving intensive insulin therapy with or without oral DM medications. e. Correctional insulin needs i. Always a need to correct for hyperglycemic excursions, despite optimal basal-bolus therapy ii. “1800 rule”: 1800/TDI = milligrams per deciliter of glucose lowering per 1 unit of rapid-acting insulin (a) For example, if TDI is 60 units, 1800/60 = 30, suggesting that 1 unit of rapid-acting insulin will reduce BG concentrations by 30 mg/dL. (b) Also called insulin sensitivity factor (c) Alternative: “1500 rule” when using regular human insulin (i.e., 1500/TDI) iii. More patient-specific than traditional sliding-scale insulin f. Continuous glucose monitoring (CGM) i. Used with or without insulin pumps ii. Real-time CGM (continuously transmits glucose data to sensor or smart device) iii. Intermittent CGM (requires scanning by a sensor to view glucose data) g. Continuous subcutaneous insulin infusion (insulin pump) i. Device allows patient-specific hourly basal dosing and bolus insulin dosing. ii. Uses rapid-acting insulins iii. Requires patient education and carbohydrate counting iv. Used in conjunction with continuous glucose monitoring devices. Technology is rapidly advancing (newest systems, called “hybrid closed-loop systems,” act almost as an artificial pancreas). h. Assessing therapy and dosage adjustment i. Know the goals for fasting and postprandial glucose concentrations. ii. Identify when patient is at goal and not at goal (hypoglycemia or hyperglycemia). Look for consistent trends rather than isolated events. iii. Identify which insulin affects problematic glucose concentrations. iv. Adjust insulin dosage or patient behavior accordingly. v. Same process for treating T2D applies (see text that follows) 3. Amylin analog a. Mechanism of action: Amylin is cosecreted with insulin and has effects similar to those of GLP-1 described in the text that follows. b. Pramlintide is currently the only agent in this class available in the United States. Pramlintide can be used in either T1D or T2D as adjunctive therapy in patients receiving insulin. c. Dosing i. T1D (a) Initial: 15 mcg subcutaneously immediately before main meals (b) Must reduce dosage of preprandial rapid-acting, short-acting, or combination insulin products by 50% ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-231 Endocrine and Metabolic Disorders (c) Maximal daily dosage is 60 mcg with each meal. (d) Dosage should be titrated in 15-mcg increments, as tolerated, but no more rapidly than every 3 days. ii. T2D (a) Initial: 60 mcg subcutaneously immediately before main meals (b) Must reduce preprandial insulins by 50% (c) Maximal daily dosage: 120 mcg with each meal (d) Dosage should be titrated in 60-mcg increments, as tolerated, but no more rapidly than every 3–7 days. iii. Use of prefilled pens is strongly recommended, when possible, rather than a syringe and vial, to reduce the 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. Boxed warning for severe hypoglycemia, especially in patients with T1D ii. Nausea, vomiting, anorexia, headache e. Contraindications and 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. Effective at controlling postprandial glucose excursions Patient Cases 9. A 55-year-old man with T2D for 6 months has been receiving metformin 1000 mg twice daily since his diagnosis. His A1C today is 8.2%. His morning fasting blood glucose (FBG) readings are consistently at goal. His after-meal glucose readings average 210–230 mg/dL. The patient states that he is worried about his weight and does not want to add a medication that might increase it. Which would be most appropriate for this patient? A. Glyburide. B. Liraglutide. C. Pioglitazone. D. Insulin glargine. 10. A 66-year-old man has had T2D for 4 years. His A1C today is 7.7%. He has altered his diet and states that he has been exercising regularly for months. He takes metformin 1000 mg twice daily. Which would best 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 bromocriptine 0.8 mg at bedtime. D. Add sitagliptin 100 mg once daily to his metformin therapy. I. Therapeutic Management of T2D 1. Given the progressive nature of T2D, a stepwise approach is usually needed. 2. ADA treatment recommendations for hyperglycemia emphasize a patient-centered approach to care, considering patient preferences, needs, and values. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-232 Endocrine and Metabolic Disorders 3. Metformin remains the initial drug of choice, unless contraindicated or adverse effects preclude its use or if improvements in exercise and diet early after diagnosis fail to control hyperglycemia. (Consider combination therapy of metformin with the medications listed in the text that follows if baseline A1C is 1.5% or greater above personal goal A1C.) 4. If metformin monotherapy fails to allow the patient to attain or maintain glycemic control, adding other agents is based on several criteria and weighs the advantages and disadvantages of the various oral and injectable agents. a. Efficacy in lowering A1C (also focus on ability to lower fasting or postprandial glucose concentrations or both) b. Existing comorbidities. The following agents that may be added to or replace metformin for patients with established cardiovascular disease, heart failure, or renal insufficiency: i. Cardiovascular disease: Consider GLP-1 agonist or SGLT-2 inhibitor ii. Heart failure or chronic kidney disease: Consider SGLT-2 inhibitor c. Risk of hypoglycemia d. Effects on weight e. Adverse effect profile f. Cost g. Oral or injection patient preference 5. Sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium glucose cotransporter-2 (SGLT-2) inhibitors, GLP-1, GIP/GLP-1 agonists, and basal insulin are preferred to less efficacious options or agents with a higher adverse risk profile. 6. Adding injectable medications to existing oral DM agents a. ADA recommends GLP-1 agonists as preferred to insulin unless extreme or symptomatic hyperglycemia is present. i. Because of a mildly improved A1C reduction with GLP-1 agonists compared with insulin therapies ii. GLP-1 agonists have a lower risk of hypoglycemia and are associated with weight loss. b. Consider addition of a basal insulin / GLP-1 agonist combination or basal/bolus insulin regimen when significant hyperglycemia exists. ADA suggests adding either early in therapy if: i. A1C greater than 10% or ii. A1C is greater than 2% above goal c. Weight-based dosing: For example, 0.1–0.2 unit/kg/day of basal insulin (higher dosages if significant hyperglycemia exists) d. Can increase basal insulin according to fasting glucose concentrations e. Can add GLP-1 agonist or SGLT-2 inhibitor if weight gain is a concern or bolus insulin to one or more meals if postprandial glucose is a concern after initiating basal insulin f. Insulin secretagogues should be lowered in dosage or discontinued altogether when bolus insulin added to reduce risk of hypoglycemia g. Thiazolidinediones should be lowered or discontinued when basal or bolus insulin is added to the regimen because of the increased risk of edema. 7. 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 T1D described earlier b. The TDI requirements in T2D are usually much higher than in T1D because of insulin resistance. J. Therapeutic Agents in T2D 1. Metformin (biguanide) a. Mechanism of action: Reduces hepatic gluconeogenesis; also favorably affects insulin sensitivity and, to a lesser extent, intestinal absorption of glucose ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-233 Endocrine and Metabolic Disorders b. c. 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 Adverse effects i. Common: Nausea, vomiting, diarrhea, epigastric pain ii. Less common: Decrease in vitamin B12 concentrations (monitor periodically), lactic acidosis (rare) iii. Signs or symptoms of lactic acidosis include acidosis, nausea, vomiting, increased respiratory rate, abdominal pain, shock, and tachycardia. d. Contraindications and precautions (because of risk of lactic acidosis) i. Renal impairment (contraindicated because of increased risk of lactic acidosis) (a) Discontinue if eGFR is less than 30 mL/minute/1.73 m2, and initiating if eGFR is 30–45 mL/minute/1.73 m 2 is not recommended. Assess benefit of continuing use in patients already prescribed metformin if eGFR is 30–45 mL/minute/1.73 m 2 and consider a 50% dose reduction. (b) Monitor renal function every 3–6 months in patients with eGFR of 45–60 mL/minute/ 1.73 m2 and every 3 months if 30–45 mL/minute/1.73 m2 ii. Age 80 or older (use caution and carefully assess renal function) iii. High risk of cardiovascular event or hypoxic state iv. Hepatic impairment v. Interrupt therapy in patients with eGFR of 30–60 mL/minute/1.73 m2 if undergoing procedures using iodinated contrast dye because of risk of nephrotoxicity. Reinitiate after 48 hours and after normal SCr 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 2. Sulfonylureas a. Mechanism of action: Bind to receptors on pancreatic β-cells, leading to membrane depolarization, with subsequent stimulation of insulin secretion (insulin secretagogue) b. First-generation agents seldom used today (e.g., chlorpropamide, tolbutamide) c. Second-generation agents (e.g., glyburide, glipizide, glimepiride). Dosage titration: Can increase at weekly intervals, as necessary d. Adverse effects i. Common: Hypoglycemia, weight gain ii. Less common: Rash, headache, nausea, vomiting, photosensitivity iii. Rare: Lactic acidosis e. Contraindications and 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 older adults 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. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-234 Endocrine and Metabolic Disorders Table 4. Second-Generation Sulfonylurea Dosing Strategies Drug Glyburide (not micronized) Glyburide (micronized) Glipizide Glimepiride Initial Dosage 2.5–5.0 mg once or twice daily 1.5–3 mg once or twice daily 5 mg once or twice daily (once daily with extended release) 1–2 mg once daily Maximum Daily Dosage (mg) 20 12 40 (little improved efficacy > 20 mg/day) 8 3. Meglitinides a. Mechanism of action: 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 d. Dosing i. Repaglinide (a) Initial: 0.5–1 mg 15 minutes before meals (b) Maximal daily dosage: 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 and precautions i. Hypersensitivity ii. Caution in concomitant use of repaglinide and gemfibrozil: Can lead to greatly increased repaglinide concentrations g. Efficacy i. 0.5%–1.5% A1C reduction (repaglinide reduces A1C more than nateglinide) ii. Most effective on postprandial glucose excursions 4. Thiazolidinedione (often called glitazones or TZDs) 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. Dosing i. Pioglitazone (a) Initial: 15 mg once daily (b) Maximal daily dosage: 45 mg ii. Dosage titration is slow, and the maximal effect of a dosage change may not be observed for 8–12 weeks. c. Adverse effects i. Weight gain ii.  Fluid retention (particularly peripheral edema) is worse with insulin use and is dosedependent. Edema is less responsive to diuretic therapy. Macular edema can result. iii. Risk of proximal bone fractures; use caution in patients with existing osteopenia or osteoporosis (discontinuation reduces risk) ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-235 Endocrine and Metabolic Disorders iv. Possible risk of bladder cancer with pioglitazone (dosage and duration of use dependent). Data are contradictory. v. Increased risk of heart failure (a) Boxed warning (b) More than a 2-fold higher relative risk, although absolute risk is quite small d. Contraindications and precautions i. Hepatic impairment ii. Class III/IV heart failure (symptomatic heart failure) iii. Existing fluid retention e. Efficacy i. 0.5%–1.4% A1C reduction ii. May help improve HDL as well 5. DPP-4 inhibitors a. Mechanism of action: Inhibit the breakdown of 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 dosage with CrCl if 30–49 mL/minute/or greater to 50 mg once daily. (b) Reduce dosage with CrCl less than 30 mL/minute to 25 mg once daily. ii. Saxagliptin: 5 mg once daily (a) Reduce dosage with CrCl of 50 mL/minute or less to 2.5 mg once daily. (b) Reduce dosage when coadministered with strong CYP3A4/5 inhibitor (e.g., ketoconazole) to 2.5 mg once daily. iii. Linagliptin: 5 mg once daily (no dosage adjustment for renal impairment) iv. Alogliptin: 25 mg once daily (a) Reduce dosage with CrCl of 30–59 mL/minute to 12.5 mg once daily. (b) Reduce dosage with CrCl less than 30 mL/minute to 6.25 mg once daily. c. Adverse effects i. Upper respiratory and urinary tract infections, headache, severe joint pain ii. Hypoglycemia with monotherapy is minimal, but frequency is increased with concurrent sulfonylurea therapy (can lower dosage of sulfonylurea when initiating). iii. Sitagliptin has had some postmarketing reports of acute pancreatitis, angioedema, StevensJohnson syndrome, and anaphylaxis. iv. Safety studies of saxagliptin and, to a lesser extent, alogliptin (but not sitagliptin or linagliptin) have shown an increased risk of heart failure hospitalization. In 2017, the FDA recommended warnings to package labeling of all DPP-4 inhibitors. d. Contraindications and precautions i. Previous hypersensitivity to the agents ii. History of pancreatitis e. Efficacy: 0.5%–0.8% reduction in A1C, considered weight neutral 6. SGLT-2 inhibitor a. Mechanism of action: Increases urinary glucose excretion by blocking normal reabsorption in the proximal convoluted tubule; has some effect on delaying GI glucose absorption b. Dosing i. Canagliflozin (a) 100 mg once daily before the first meal of the day (b) Maximal daily dosage: 300 mg (c) Reduce dosage with eGFR of 30–59 mL/minute/1.73 m 2 to 100 mg daily. (d) Discontinue or do not initiate if eGFR is less than 30 mL/minute/1.73 m 2. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-236 Endocrine and Metabolic Disorders ii. Dapagliflozin (a) 5 mg once daily in the morning (with or without food) (b) Maximal daily dosage: 10 mg (c) Discontinue or do not initiate if eGFR is less than 45 mL/minute/1.73 m 2. iii. Empagliflozin (a) 10 mg once daily in the morning (with or without food) (b) Maximal daily dosage: 25 mg (c) Discontinue or do not initiate if eGFR is less than 45 mL/minute/1.73 m 2. iv. Ertugliflozin (a) 5 mg once daily in the morning (with or without food) (b) Maximal daily dosage: 15 mg (c) Discontinue or do not initiate if eGFR is less than 60 mL/minute/1.73 m 2. c. Adverse effects i. Increased urination ii.  Urinary tract infections iii. Genital mycotic infections (more common in females) iv. Hypotension v. Increased hypoglycemia risk with concomitant insulin or insulin secretagogue vi. Class is linked with rare cases of euglycemic DKA and Fournier gangrene. vii. Possible increased bone fracture risk, decreased bone mineral density, and foot or leg amputation with canagliflozin d. Contraindications and precautions i. Significant renal impairment (varies by agent, as stated earlier) ii. Suggested to ensure euvolemia before initiating agent, given its diuretic effect especially in older adults, patients with existing renal impairment or already low blood pressure, or patients receiving diuretics iii. Consider factors that could predispose the patient to acute kidney injury (e.g., low blood volume, chronic kidney insufficiency, heart failure, or medications that could alter kidney function). iv. Agent should be discontinued before any surgery to reduce the risk of ketoacidosis (3 days before with canagliflozin, dapagliflozin, and empagliflozin and 4 days before with ertugliflozin). e. Efficacy i. 0.3%–1.0% reduction in A1C ii. Effect on both fasting and postprandial glucose concentrations iii. Mild weight loss iv. Empagliflozin, dapagliflozin, and canagliflozin can reduce cardiovascular morbidity in patients with T2D and established cardiovascular disease and may improve renal outcomes. v. Canagliflozin or dapagliflozin in patients with significant urine albumin excretion and renal insufficiency reduces the risk of end-stage renal disease, doubling of SCr, or renal death. vi. All agents within the class have been shown to reduce heart failure admissions in patients with T2D with or without a history of heart failure. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-237 Endocrine and Metabolic Disorders Patient Case 11. A 66-year-old man is given a diagnosis today of T2D. Two weeks ago, his A1C was 7.5% and SCr was 1.8 mg/ dL (eGFR 25 mL/minute/1.73 m2). 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 is best to initiate? A. Linagliptin. B. Pioglitazone. C. Exenatide. D. Metformin. 7. GLP-1 analogs 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. Approved agents: Exenatide, liraglutide, dulaglutide, lixisenatide, and semaglutide c. Dosing i. Exenatide (a) Twice-daily formulation (pen) (1) Initial: 5 mcg subcutaneously twice daily, administered no more than 60 minutes before morning and evening meals (2) Maximal dosage: 10 mcg twice daily (3) Dosage titration from 5 mcg to 10 mcg twice daily after 1 month, if tolerated (b) Once-weekly formulation (single-dose tray or pen, each containing lyophilized powder and diluent) (1) 2 mg subcutaneously once weekly (2) Powder must be reconstituted by patient immediately before injection. ii. Liraglutide (pen) (a) 0.6 mg subcutaneously once daily for 1 week (regardless of mealtime) (b) Dosage titration from 0.6 to 1.2 mg/day, if tolerated (c) Maximal daily dosage: 1.8 mg/day iii. Lixisenatide (pen) (a) Initial dose: 10 mcg once daily for 14 days (b) Maintenance dose: 20 mcg once daily iv. Dulaglutide (pen and single-dose syringe) (a) 0.75 mg subcutaneously once weekly (b) Dosage titration to 4.5 mg once weekly for additional glycemic control v. Semaglutide (pen and single-dose syringe and oral formulation) (a) 0.25 mg subcutaneously once weekly (b) Dosage titration to 2 mg once weekly at monthly intervals for additional glycemic control (c) Oral formulation is dosed starting with 3 mg once daily and increased at monthly intervals to a maximum dose of 14 mg daily. d. Adverse effects i. Nausea, vomiting, diarrhea common, but can subside or cease over time ii. Hypoglycemia common with concurrent sulfonylurea or insulin (consider reduction in sulfonylurea or insulin dose) iii. Postmarketing reports of pancreatitis and acute renal failure or impairment ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-238 Endocrine and Metabolic Disorders e. Contraindications and precautions i. Impaired renal function: CrCl less than 30 mL/minute for either exenatide formulation; less specific for liraglutide. No dose adjustment necessary with semaglutide ii. Caution with a history of severe GI tract disorder, particularly gastroparesis iii. History of pancreatitis iv. For liraglutide, semaglutide, dulaglutide, once-weekly exenatide: 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%–1.5% reduction in A1C ii. Effects on postprandial hyperglycemia better than on fasting glucose concentrations with once- or twice-daily formulations iii. Improved A1C, fasting glucose reduction, and nausea or vomiting with once-weekly than with twice-daily exenatide formulation iv. Modest weight loss v. Liraglutide, dulaglutide, exenatide, and semaglutide have been shown to reduce some cardiovascular outcomes in high-risk patients, whereas lixisenatide has not, question whether class effect because populations studied in cardiovascular outcomes trials differed greatly with respect to percentages of those with existing cardiovascular disease 8. GLP-1/glucose-dependent insulinotropic polypeptide agonist a. Mechanism of action: Similar to GLP-1 agonists above b. Tirzepatide is the only agent currently approved for treatment of T2D. c. Dosing i. Initial: 2.5 mg subcutaneously once weekly ii. Increase at monthly intervals to 5, 10, or 15 mg once weekly d. Adverse effects: Similar to GLP-1 agonists e. Contraindications and precautions: Similar to GLP-1 agonists f. Efficacy i. 2.0%–2.3% reduction in A1c, also decreases body weight ii. Targets both fasting and postprandial glucose excursions 9. α-Glucosidase inhibitors a. Mechanism of action: Slows the absorption of glucose from the intestine to 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 three times daily at each meal ii. Maximum daily dosage: 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 with high doses of acarbose e. Contraindications and precautions: Inflammatory bowel disease, colonic ulcerations, intestinal obstruction f. Efficacy i. 0.5%–0.8% reduction in A1C, also shown to decrease body weight ii. Targets postprandial glucose excursions iii. Might not be as effective in patients using low-carbohydrate diets ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-239 Endocrine and Metabolic Disorders 10. Bile acid sequestrant: a. Mechanism of action i. Bile acid sequestrant used primarily for cholesterol management. Its mechanism to reduce serum glucose concentrations is not clearly understood. Colesevelam is thought to be an antagonist to the farnesoid X receptor, which subsequently reduces hepatic gluconeogenesis. By reducing bile acid absorption, colesevelam reduces farnesoid X receptor activity. ii. Used in conjunction with insulin or oral DM medications b. Colesevelam is the only studied and approved drug in this class. c. Dosing: Six 625-mg tablets once daily or three 625-mg tablets twice daily d. Adverse effects: Constipation, dyspepsia, nausea, myalgia e. Contraindications and precautions i. Contraindicated in patients with a history of bowel obstruction or serum triglyceride concentrations greater than 500 mg/dL ii. Caution in patients with swallowing disorders (large pill), dysphasia, gastric mobility disorders, and serum triglyceride concentrations greater than 300 mg/dL f. Efficacy: 0.3%–0.5% reduction in A1C 11. Bromocriptine a. Mechanism of action: Not clearly understood. Agonist for dopamine receptor D2 is thought to reset circadian rhythm, which can reduce caloric intake and storage. Other effects may be through α1-antagonism, α2-agonistic properties, and modulation of serotonin and prolactin. b. Dosing i. Initial: 0.8 mg once daily on waking; take with food (increases bioavailability) ii. Maximal daily dosage: 4.8 mg iii. Titrate weekly by 0.8 mg/day as tolerated and according to response. iv. Tablet strength differs from generic formulations currently on the market. c. Adverse effects: Nausea, somnolence, fatigue, dizziness, vomiting, headache, orthostatic hypotension, syncope d. Contraindications and precautions i. Can limit the effectiveness of agents used to treat psychosis or exacerbate psychotic disorders ii. Should not be used in nursing mothers or patients with syncopal migraines iii. Concomitant use with dopamine antagonists (e.g., neuroleptic agents) can limit the efficacy of both agents. e. Efficacy (Table 5) i. 0.1%–0.6% reduction in A1C ii. Possible cardiovascular benefit ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-240 Endocrine and Metabolic Disorders Table 5. Comparison of Therapies for Type 2 Diabetes Hyperglycemia Added to Metformin Agent or Class Primary Glycemic Effect Sulfonylurea Benefits Limitations and Precautions Fasting and prandial Efficacy Cost Meglitinide Prandial Prandial focus Use in kidney impairment Pioglitazone Fasting and prandial α-Glucosidase inhibitor Prandial DPP-4 inhibitor Prandial Improved insulin sensitivity and pancreatic function Low risk of hypoglycemia Possible cardiovascular benefit Cost No systemic absorption Prandial focus Weight loss Well tolerated Weight neutral Weight gain Hypoglycemia risk Hastens b cell dysfunction Hypoglycemia risk Weight gain Mealtime dosing Weight gain and edema Risk of heart failure Risk of osteoporosis Possible bladder cancer risk? GLP-1 agonist and GIP/GLP-1 agonist Once- or twice-daily formulations have prandial focus Once-weekly formulations affect both fasting and prandial Colesevelam Prandial Bromocriptine Fasting and prandial SGLT-2 inhibitors Fasting and prandial Amylin agonist Prandial Insulin Basal: Fasting Bolus: Prandial Greater effect on prandial glucose Weight loss Efficacy Improves pancreatic function? Cardiovascular benefit (liraglutide, semaglutide, dulaglutide, and exenatide) Lipid benefits No systemic absorption Low risk of hypoglycemia Possible cardiovascular benefit Low risk of hypoglycemia Efficacy Weight loss Possible heart failure, cardiovascular, and renal benefit Modest weight loss Efficacy on postprandial glucose Significant A1C reduction Flexibility in dosing strategies and titration GI adverse effect profile Mealtime dosing Modest A1C effect Possible pancreatitis risk? Modest A1C effect Possible increased heart failure risk (saxagliptin) Cost Nausea and vomiting Injection-site effects Questionable pancreatitis or thyroid cancer risk? Cost Large pill size and burden GI adverse effect profile Small decrease in A1C Avoid with high TG Small decrease in A1C Central nervous system adverse effects Urinary tract and genital infections Diuresis Euglycemic DKA? High risk of hypoglycemia Must be taken with insulin Frequent injections Injection-site effects GI adverse effects Hypoglycemia Weight gain Injection-site effects DKA = diabetic ketoacidosis; DPP-4 = dipeptidyl peptidase-4; GI = gastrointestinal; GLP = glucagon-like peptide; SGLT = sodium glucose cotransporter. Information adapted from: Davies M, D’Alessio D, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018;41:2669701; Garber A, Abrahamson M, Barzilay J, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm-2018 executive summary. Endocr Pract 2018;24:91-120. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-241 Endocrine and Metabolic Disorders K. Treatment of Inpatient DM (non–critically ill population) 1. Joint guidelines from the ADA and AACE. The Endocrine Society also has guidelines. 2. Strong association between admission hyperglycemia and worse inpatient outcomes and length of stay. Outcomes are worse in those who have stress-related hyperglycemia or are not known to have diabetes previously. 3. Glycemic goal: 140–180 mg/dL 4. Treatment a. Assess glucose concentrations before meals and at bedtime, if eating (every 4–6 hours if taking nothing by mouth [NPO] or receiving continuous tube feedings). b. Threshold for initiating therapy is 180 mg/dL or greater. c. According to the guidelines, subcutaneous insulin administration is the most practical way to improve hyperglycemia. d. Oral diabetes agents are generally not recommended unless the patient is clinically stable and eating regularly, and no significant precautions or contraindications for their use exist. e. Use of sliding-scale insulin alone is not recommended. f. Basal-bolus insulin therapy as described earlier in the treatment of T1D is recommended unless the patient is NPO. If NPO, use basal insulin alone VII. TREATMENT OF DIABETES MELLITUS COMPLICATIONS Patient Case 12. A patient with newly diagnosed T2D is screened for diabetic nephropathy. The following laboratory values are obtained today: blood pressure 129/78 mm Hg, heart rate 78 beats/minute, urine albumin/creatinine 27 mg/g, and estimated CrCl 94 mL/minute/1.73 m2. Which would be the most appropriate treatment strategy? A. No change in therapy is warranted. B. Add an angiotensin-converting enzyme (ACE) inhibitor. C. Add a thiazide-like diuretic. D. Reduce daily protein intake. A. Hypoglycemia 1. Degree of intervention depends on glucose concentrations and presence of symptoms. 2. Symptoms are patient-specific but can include anxiousness, sweating, nausea, tachycardia, hunger, and clammy skin. 3. Consequences of significant hypoglycemia are most worrisome in the very young, older adults, and those with established heart disease. 4. Assess at every clinic visit, including frequency, causes, or risks of such. 5. Classification (according to ADA recommendations) a. Level 1: Plasma glucose of 70 mg/dL or less with or without symptoms b. Level 2: Clinically significant hypoglycemia: Plasma glucose less than 54 mg/dL c. Level 3: A severe event characterized by altered mental and/or physical status requiring assistance 6. Treatment a. Mild to moderate hypoglycemia i. Oral ingestion of 15–20 g of glucose or equivalent ii. Repeat glucose concentration in 15 minutes and, if still less than 70 mg/dL, repeat ingestion of glucose. iii. Once glucose is normalized, ingest snack or meal. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-242 Endocrine and Metabolic Disorders b. Clinically significant hypoglycemia (altered consciousness, needs assistance from others) i. Glucagon 1 mg subcutaneously or intramuscularly or 3 mg by nasal inhalation ii. Intravenous dextrose if patient does not respond to glucagon iii. Raise glucose targets for several weeks. B. Diabetic Ketoacidosis 1. More common in T1D but can occur in T2D 2. Usually occurs because of a precipitating factor that 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 and symptoms: Polyuria, polydipsia, vomiting, dehydration, weakness, altered mental status, coma, abdominal pain, Kussmaul respirations, tachycardia, hyponatremia, hyperkalemia 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 regular insulin: 0.1 unit/kg iii. Intravenous infusion (a) 0.1 unit/kg/hour regular insulin (increase if not a 50- to 75-mg/dL decrease 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 attained 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 of 150–200 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. Potassium 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. Potassium 20–30 mEq/hour if baseline less than 3.3 mEq/L e. Intravenous bicarbonate if serum pH less than 6.9 (addition of bicarbonate is somewhat controversial) 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 greater than 7.3 ii. Serum bicarbonate of 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/creatinine ratio, starting at diagnosis in T2D and after 5 or more years in T1D. a. Normal: Less than 30 mg/g (or micrograms per milligram) b. Increased urinary albumin excretion (albuminuria) 30 mg/g or greater ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-243 Endocrine and Metabolic Disorders c. Two of three specimens greater than 30 mg/g obtained over 3–6 months is consistent with a diagnosis of albuminuria d. The ADA no longer uses the terms microalbuminuria and macroalbuminuria. 2. Estimate renal function yearly (CrCl or eGFR). 3. ACE inhibitors or ARBs are considered the initial treatment of choice if urine albumin/creatinine concentrations are greater than 30 mg/g. 4. Dietary protein restriction as renal function declines 5. Canagliflozin or dapagliflozin in patients with decreased renal function and significantly elevated albuminuria reduces decline in eGFR and risk of developing end-stage renal disease 6. If the patient is unable to tolerate or has contraindication to an SGLT2 inhibitor, consider adding the nonsteroidal mineralocorticoid antagonist finerenone. D. Retinopathy 1. Screen annually with dilated and comprehensive eye examinations, starting at diagnosis in T2D and after 5 or more years in T1D. 2. Frequency can be reduced to every 2–3 years after one or more normal examinations. 3. Appropriately control glucose concentrations, cholesterol, and blood pressure. 4. Severe forms of retinopathy (e.g., proliferative retinopathy, macular edema) can be treated with intravitreous steroids or antivascular endothelial growth factor with or without photocoagulation. E. DM Neuropathies 1. Can have nerve damage in any area of the body, but commonly affects the lower extremities 2. Screen for distal polyneuropathy a. Screen after 5 years in T1D and at diagnosis in T2D, then yearly thereafter b. Diminished sensitivity is a significant risk factor for diabetes-related foot ulcers and increases the need for frequent visual inspection by patients, if it exists. 3. Symptoms are patient-specific but can include numbness, burning, tingling sensation, or pain. 4. Treatment of neuropathies should focus on glycemic control to minimize disease progression. Therapies for symptomatic improvement do not prevent progression. 5. Neuropathic pain therapy a. ADA recommendations consider duloxetine, gabapentin, or pregabalin as initial therapy. b. 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. c. Anticonvulsants (gabapentin, lamotrigine, pregabalin) i. Comparative data on gabapentin and pregabalin against tricyclic antidepressants show similar efficacy with fewer adverse effects. Adverse effect profile is still significant (e.g., fatigue, dizziness). ii. Pregabalin is the only anticonvulsant approved for use in DM neuropathic pain. d. Selective serotonin reuptake inhibitor/selective serotonin and norepinephrine reuptake inhibitor (duloxetine, paroxetine, citalopram, venlafaxine) i. Duloxetine is the only approved agent in this category. ii. Duloxetine data compared with amitriptyline data show similar efficacy and expected higher anticholinergic adverse effects with amitriptyline. iii. Duloxetine may provide better pain reduction, with tolerability similar to that of pregabalin. e. Tramadol/acetaminophen: As effective as gabapentin; different adverse effect profile f. Opioids: Tapentadol extended release is the only approved agent in this class; no head-to-head efficacy studies ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-244 Endocrine and Metabolic Disorders g. Topical capsaicin is an alternative therapy for those with focal pain. Would not use if pain is more diffuse or widespread 6. Gastroparesis therapy a. Autonomic neuropathy causes nausea and vomiting after meals because of delayed gastric emptying. b. Nonpharmacologic strategies i. More frequent but smaller meals ii. Homogenize food iii. Decrease fat and fiber in diet iv. Gastric pacemaker c. Pharmacologic treatment i. Metoclopramide: 10 mg orally or 15 mg intranasally before meals; risk of tardive dyskinesia or extrapyramidal reactions, chronic use should assess the benefit-risk of continued therapy ii. Erythromycin: 40–250 mg before meals for up to 1 month F. Cardiovascular Disease 1. Most common cause of morbidity and mortality and 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 the blood pressure and lipid goals described earlier. 4. Blood pressure management a. Often requires more antihypertensive medications b. Hypertensive regimen should include an ACE inhibitor, ARB, dihydropyridine calcium channel blocker, or thiazide-like diuretic. c. If both hypertension and increased urine albumin excretion are present, first-line therapy is an ACE inhibitor or an ARB. d. Administration of at least one antihypertensive in the evening may improve blood pressure and reduce cardiovascular outcomes. 5. Lipid management (according to the ADA) a. Assess fasting lipid profile annually or as needed to monitor adherence. b. Statin therapy recommendations are based on age and cardiovascular risk. i. Moderate-dose statin therapy is recommended for all patients age 40–75 without established cardiovascular disease. ii. High-dose statin therapy should be considered for those with multiple cardiovascular risk factors. iii. High-dose statin therapy is recommended for all patients with established cardiovascular disease (e.g., previous cardiovascular event or acute coronary syndrome) or several existing cardiovascular risk factors. iv. For patients with atherosclerotic cardiovascular disease and LDL greater than 70 mg/dL despite statin therapy, consider additional LDL-lowering therapy. v. Statin doses are consistent with the ACC/AHA lipid guidelines. 6. Antiplatelet therapy a. Low-dose aspirin (75–162 mg/day) i. With existing cardiovascular disease ii. Consider as part of primary prevention if at an increased cardiovascular risk b. Clopidogrel for those intolerant of aspirin therapy 7. Consider adding a GLP-1 agonist or SGLT-2 inhibitor with proven cardiovascular benefit (especially in patients with known heart disease). a. Not all agents in each class have shown benefit in reducing cardiovascular outcomes. b. SGLT-2 inhibitors have shown a reduction in heart failure admissions in patients with or significantly at risk of cardiovascular disease. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-245 Endocrine and Metabolic Disorders c. GLP-1 agonists have not shown a reduction in heart failure admissions. G. Preventive Immunizations 1. Annual influenza vaccine 2. Pneumococcal pneumonia vaccination (PPSV23) 3. Hepatitis B vaccine VIII. DIABETES INSIPIDUS A. Diabetes insipidus (DI) is usually a result of decreased production of antidiuretic hormone, also known as vasopressin, in central DI, or a lack of antidiuretic hormone effect in the kidneys (nephrogenic DI). B. Classification 1. Central or neurogenic a. Idiopathic b. Trauma (brain injury) c. Neoplasm d. Hypodipsia e. Genetic abnormality 2. Nephrogenic a. Genetic abnormality b. Acquired (more common) i. Drug induced (e.g., lithium, amphotericin B, foscarnet, cidofovir) ii. Kidney disease (e.g., polycystic kidney disease, obstruction) iii. Electrolyte disorder (hypercalcemia, hypokalemia) C. Diagnosis 1. Elevated urine volume (greater than 3 L/day) 2. Decreased urine osmolarity (less than 200 mOsm/kg) 3. Response to water deprivation (may help differentiate between nephrogenic and central etiology in non–critically ill patients) D. Signs and Symptoms 1. Polydipsia 2. Polyuria or nocturia 3. Weakness or lethargy 4. Confusion or delirium (if severe) E. Treatment 1. Treat underlying cause, if known. 2. Central DI a. Desmopressin: 5–20 mcg intranasally once or twice daily b. Adjunctive therapies: Chlorpropamide, carbamazepine 3. Nephrogenic DI a. Thiazide diuretic b. Dietary sodium restriction c. Indomethacin ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-246