Expired activity
Please go to the PowerPak homepage and select a course.

Module 7. Endocrine Disorders

The following common endocrinologic disorders are discussed within this module:

  • Diabetes mellitus
  • Thyroid disorders
  • Adrenal disorders

Introduction

The most common endocrinologic disorder is type 2 diabetes, which will be the focus of the diabetes section discussed below. Medication management of hypothyroidism, hyperthyroidism, Cushing’s syndrome, hyperaldosteronism, and Addison’s disease is summarized in the thyroid and adrenal sections of this module.

TYPE 2 Diabetes

Overview

In 2017, over 30 million Americans, or over 9% of the US population, had diabetes mellitus (DM).1 More than 90% of diabetes cases in American adults are identified as type 2 DM. The underlying cause of this widespread condition is the lack of endogenous insulin and/or resistance to its actions.2-4 The mechanisms that cause these endogenous insulin changes provide a general method for classification of diabetes. Type 1 DM, the less common type, occurs when an autoimmune process destroys the insulin-producing β-cells of the pancreas. As a result, patients with type 1 DM have an absolute lack of insulin. These changes become evident at an early age; therefore, diagnosis of this form typically occurs at a young age. Genetic, viral, and environmental factors are possible triggers of the autoimmune process. Impaired pancreatic β-cell function and hepatocyte, muscle, and adipocyte resistance to insulin action are mechanisms that lead to the more common form of diabetes known as type 2 DM. Factors believed to increase type 2 DM risk include: age ≥ 45 years; family history; race (Native American, African American, Latino, Asian American, Pacific Islander); impaired glucose tolerance or fasting glucose; overweight or obesity; physical inactivity; hypertension; low high-density lipoprotein (HDL) cholesterol or high triglycerides; history of atherosclerotic cardiovascular disease (ASCVD); women delivering a baby over 9 pounds; and women with polycystic ovary syndrome. Diabetes that develops during pregnancy is classified as gestational diabetes and is considered a risk factor for development of type 2 DM later in life. Other mixed and rare forms of diabetes have been classified but are beyond the scope of this review.

Patients with diabetes develop hyperglycemia due to impaired insulin action and/or its unavailability.2,3 Unlike type 2 DM, the onset of symptoms is typically sudden with type 1 DM. Initial symptoms of both types can include fatigue, weight loss (more common with type 1 DM), increased hunger and thirst, and frequent urination. Owing to its pathophysiology, patients with type 1 DM often present with extremely elevated blood glucose levels and diabetic ketoacidosis at diagnosis.2-4 On the other hand, patients with type 2 DM can remain asymptomatic for years and are often diagnosed during routine lab tests or other procedures. End-organ damage to the eyes, nerves, peripheral vessels, kidneys, arteries, and heart occur when hyperglycemia is left uncontrolled long term. The risk of microvascular complications including retinopathy, neuropathy, and nephropathy can be reduced with adequate glycemic control. Diabetes is also considered a risk factor for hypertension, hyperlipidemia, and ASCVD. It has been demonstrated that with blood pressure (BP) and lipid control in patients with diabetes, ASCVD risk can be reduced. Since over 90% of diabetes cases in American adults are type 2 DM, the remainder of this review will focus on treatment, monitoring, and education of adult patients with type 2 DM.

Patients are diagnosed with type 2 DM when fasting blood glucose (FBG) is ≥ 126 mg/dL, postprandial glucose (PPG) or random glucose (with hyperglycemic symptoms) is ≥ 200 mg/dL, or glycosylated hemoglobin (A1C) is ≥ 6.5%.4 Ideally, a repeat of the same test should be conducted to establish/confirm the diagnosis. FBG is defined as no food or drink intake for at least 8 hours; PPG is measured 2 hours after a 75-g oral glucose load known as an oral glucose tolerance test. PPG is also measured by patients with diabetes to monitor blood glucose 2 hours after a meal. 

Once a diagnosis is established, appropriate goals for glycemic control should be determined. Generally, as recommended by the American Diabetes Association (ADA), providers caring for patients with type 2 DM should aim for an A1C ≤ 7%, a FBG or PPG between 80 and 130 mg/dL and a 2-hour PPG of less than 180 mg/dL.4 ADA goals for reducing ASCVD risk in type 2 DM patients include lowering BP to < 130/80 or < 140/90 mm Hg and the use of moderate- to high-intensity statin therapy to achieve a minimum of a 30% reduction in low-density lipoprotein (LDL) cholesterol. These goals may be different and should be individualized based on various patient factors such as duration of diabetes, age, comorbidities, extent of microvascular or ASCVD complications, and presence of hypoglycemic unawareness. Guidelines from the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) are slightly more stringent compared to the ADA.5 For healthy patients with a low risk of hypoglycemia, the AACE recommends an A1C goal of ≤ 6.5% and FPG and premeal glucose of < 110 mg/dL. A higher target can be set for patients with a higher risk of hypoglycemia or concomitant serious illnesses.

Treatment

Although glycemic control may initially be achieved with nonpharmacologic interventions in some patients, over time pharmacologic agents are typically required to maintain glycemic goals due to the progressive nature of type 2 DM.4-6 More often, initial management requires both interventions at diagnosis. Lifestyle modifications involve measures to promote weight loss and reduce alcohol intake. Smoking cessation is also advocated in efforts to reduce CVD risk. These interventions require consultation, monitoring, and education from professionals and should be maintained even after pharmacologic therapy is added.

Pharmacologic agents used in the management of type 2 DM are summarized in Table 1. When its use is not contraindicated, metformin is recommended as the first-line agent by both the AACE and ADA.4,6 Insulin may be used as initial therapy for patients with symptoms of hyperglycemia or considerably elevated blood glucose levels. According to the ADA, if glycemic goals are not met after 3 months on the maximum or maximally tolerated dose of metformin and the patient does not have ASCVD or chronic kidney disease (CKD), a sulfonylurea (SU), thiazolidinedione (TZD), dipeptidyl peptidase 4 inhibitor (DPP-4), sodium glucose cotransporter 2 (SGLT-2) inhibitor, glucagon-like peptide-1 (GLP-1) receptor agonist, or insulin can be added.4,6 Patients with established CKD, heart failure (HF), or ASCVD should preferentially receive a GLP-1 receptor agonist or SGLT2 inhibitor with demonstrated risk reduction for their specific comorbidity (eg, CKD, HF, or CVD) as a second agent.4-6 Meglitinides are listed by the AACE as an alternate to SUs in patients who develop SU-induced hypoglycemia or have erratic meal schedules.5 The ADA does not incorporate meglitinides into their treatment algorithms or recommendations based on the fact that they are not commonly used in the United States and do not have recent literature to support their use.4,6 Alpha-glucosidase inhibitors, colesevelam, pramlintide, and dopamine agonists are treatment options with lower efficacy and increased side effects.5,6 According to the AACE, alternative monotherapy options, in order of preference, include GLP1- receptor agonists, SGLT-2 inhibitors, DPP-4 inhibitors, TZDs, alpha-glucosidase inhibitors, and SUs or meglitinides.5 Caution with use of SUs, meglitinides, basal insulin, and TZDs is advised by the AACE as the guideline stresses the need to prevent hypoglycemia and avoid weight gain. The AACE recommends initial dual therapy in patients who present with an A1C ≥ 7.5%. In addition to the agents recommended for monotherapy, basal insulin, colesevelam, and bromocriptine are included in the hierarchical list of agents, after TZDs and before alpha-glucosidase inhibitors, to be added on as dual therapy. If needed, the addition of a third oral agent or basal insulin is the next step followed by intensive insulin treatment involving basal and rapid-acting insulin.4-6 The decision to add insulin rather than another oral agent can be made based on the degree of glycemic control needed. Both the ADA and AACE recommend addition of insulin when the A1C is > 9% despite monotherapy or use of dual agents. According to the AACE algorithm, insulin can be used as initial therapy when patients present with symptoms and have an A1C > 9%. Adverse effects such as hypoglycemia and weight gain, concomitant disease states, efficacy, cost, and patient preference should all be taken into consideration when choosing pharmacologic treatment. Use of combination tablets that contain 2 different medications may be helpful in improving adherence.

Insulin use in type 2 DM patients is typically less intensive compared to patients with type 1 DM as endogenous insulin is still present to some degree in type 2 DM patients.4-6 Use of long-acting or basal insulin is the usual first step for managing type 2 DM. After 3 to 6 months of use, the addition of rapid-acting insulin or a GLP-1 agonist may be necessary if PPG levels are not at goal. Metformin can be continued with use of basal insulin and rapid-acting insulin whereas SUs and DPP-4 inhibitors should be discontinued once more complex insulin regimens are initiated. Patients with suboptimal control despite increasing insulin doses may benefit from the addition of pioglitazone or an SGLT2 inhibitor. Patient education on glucose monitoring, injection technique, storage, hypoglycemic symptoms and treatment, and sick-day dose adjustments are crucial when initiating insulin. Characteristics of the various insulin types, including recently approved concentrated insulins and inhaled insulin, are provided in Table 2.

Patients with diabetes who have concomitant disease states should be monitored closely because a number of medications can cause hyperglycemia. Agents known to increase glucose include corticosteroids, diuretics, sympathomimetics, estrogens, protease inhibitors, isoniazid, nicotinic acid, phenothiazines, atypical antipsychotics, phenytoin, thyroid agents, and oral contraceptives.8,9

With the risk of ASCVD increased significantly in patients with diabetes, control of other risk factors is part of optimal management in these patients.4,5 Control of hypertension reduces ASCVD risk as well as microvascular complications. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are considered first-line treatments to reduce BP. These agents are also recommended in patients with diabetes who have persistent albuminuria (urinary albumin excretion > 30 mg/24 h) to slow progression of renal disease. Patients with diabetes who have overt ASCVD (regardless of age) or are ≥ 45 years and smoke, have an LDL cholesterol ≥ 100 mg/dL, hypertension, CKD, albuminuria, or a family history of premature ASCVD should receive high-intensity statin therapy, regardless of their baseline lipid levels.4 The goal for these patients is a 50% or greater reduction in LDL cholesterol from baseline. According to the ADA guidelines, patients with diabetes without overt ASCVD or under the age of 40 years or over 75 years with multiple ASCVD risk factors should receive moderate- or high-intensity statin therapy with a target LDL reduction of 30% to less than 50% reduction from baseline. Moderate intensity statin therapy is recommended for patients with diabetes who are over the age of 40 years with no risk factors. Combination treatment of statin therapy with ezetimibe or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor can be considered for patients with LDL cholesterol levels greater than 70 mg/dL despite treatment with a statin at the maximally tolerated dose. Although the ADA guideline no longer provides a specific LDL target value, the AACE does still recommend an LDL goal of either < 100 mg/dL in patients < 40 years of age or with type 2 DM and no other risk factors, < 70 mg/dL for patients with type 2 DM with ≥ 1 ASCVD risk factor, or < 55 mg/dL for patients with type 2 DM plus established CVD.5 Antiplatelet therapy with aspirin 75 to 162 mg for primary prevention of ASCVD has shown conflicting evidence, but may be considered in patients < 70 years of age with type 2 DM and increased CV risk if the benefits of aspirin therapy outweigh the potential risk of bleeding.4 Aspirin is recommended for secondary prevention in patients with established ASCVD. Clopidogrel can be used as an alternative antiplatelet agent in patients with aspirin allergy. Use of dual antiplatelet therapy for at least 1 year after an acute coronary syndrome is appropriate.

Special populations

Management of type 2 DM in elderly patients may or may not differ from younger patients with respect to target goals.4 When setting treatment goals in this population, comorbid conditions, advanced diabetes complications, cognitive status, risk of hypoglycemia, and life expectancy are factors to consider. Additionally, initial medication doses may need to be lowered and adjusted for comorbid conditions such as renal impairment. At a minimum, hyperglycemia should be controlled to a level that avoids acute symptoms. With higher rates of obesity and type 2 DM in children, treatment of this population faces challenges with respect to long-term safety of oral pharmacologic agents.10,11 Many of the agents used for treatment have little efficacy data on use in children. A practice guideline from the American Academy of Pediatrics recommends use of insulin in children with random glucose values ≥ 250 mg/dL or A1C > 9%.11 In other children in whom type 1 DM has been excluded, lifestyle intervention and metformin treatment are recommended first-line. Use of other specific oral agents is not addressed. Treatment of gestational diabetes involves close glucose monitoring, dietary changes, physical activity, and use of insulin if needed.4 Specific glycemic targets have been established and are more stringent than glycemic goals for type 2 DM.

Monitoring Parameters

The A1C is a measure of glycemic control over a period of approximately 3 months.4 During initial treatment, it should be monitored every 3 months until target values are achieved.4,5 Thereafter, semi-annual measurement may be sufficient. SMBG (SMBG) can be helpful to patients to determine the impact of dietary changes, physical activity, and medications on glycemic control. Historically, SMBG has been recommended in patients with type 2 DM taking oral agents, basal insulin, or intensive insulin treatment to assist in management of blood glucose. However, several studies have shown that SMBG in patients treated with noninsulin agents may not be cost-effective or lead to clinically significant reductions in A1C.4 Additionally, the current evidence is inadequate to inform clinicians as to when SMBG should be recommended and how often patients on oral therapy or less intensive insulin regimens (eg, basal insulin) should test their glucose. In patients receiving basal insulin, SMBG has shown some benefit in lowering the A1C when used to test fasting glucose levels to assist with management of insulin dosing. SMBG remains an important component in the management of patients on intensive insulin regimens; patients should monitor their glucose up to 6 to 10 times per day, based on individual needs. More recently, continuous glucose monitoring (CGM) has gained popularity as a method to assess patient glucose.4,5 Continuous glucose monitors are devices that measure interstitial glucose (either on a continuous basis or intermittently). Professional CGMs are recommended in patients that have received at least 3 months of treatment for hyperglycemia and have not yet met their target, or in those that require treatment with agents that carry a risk for hypoglycemia. Personal CGM devices (owned by the patient) can be used in patients on intensive insulin therapy, those with repeated hypoglycemia, or those with hypoglycemia unawareness. Signs and symptoms of hypoglycemia are crucial monitoring parameters to aid in medication adjustments. Oral glucose (15-20 g) should be used for treatment of hypoglycemic episodes in conscious patients.4 Patients with severe hypoglycemia should receive glucagon administered by a trained caregiver. Other monitoring parameters, related to complications of diabetes, include BP (at every visit), lipids (at least annually for most patients), renal albumin excretion (annually), ophthalmic exams (at least every 2 years), and foot exams (annually). Appropriate vaccinations should be provided including annual influenza vaccines to all adult patients with diabetes.

Table 1. Medications Used in the Treatment of Type 2 Diabetes2-6,7,8,11-17
Drug Class Dose Mean HbA1C decrease Common Adverse Events Drug interactions Comments
First-line agents
Biguanides Metformin:

Regular-release: 500-850 mg 1-3 times daily after a meal up to a maximum of 2500 mg or 2550 mg daily

Extended-release: 500 mg every evening up to 2000 mg daily		 1.5%- 2% Diarrhea

Abdominal discomfort
  • Cimetidine: increases metformin concentrations by competing for renal tubular secretion
  • Alcohol: potentiates risk of lactic acidosis
  • Iodinated contrast media: can lead to acute renal failure and increase risk of lactic acidosis; withhold metformin before procedure and for at least 48 hours after until serum creatinine is normalized
  • Titrate every 2 weeks or as tolerated
  • Abdominal symptoms may be alleviated by reducing the dose and with slow titration
  • Avoid use in patients with severe renal/hepatic impairment to avoid accumulation that can lead to lactic acidosis
  • In April 2016, the FDA approved revised labeling for metformin use in patients with renal impairment. Metformin should not be used in patients with an eGFR of < 30 mL/min/1.73 m2 and should not be started in patients with eGFR between 30 and 45 mL/min/1.73 m2. If eGFR falls below 45 mL/min/1.73 m2 in patients already taking metformin, benefit to risk of continuation should be considered
  • Can be used in patients with stable HF
Insulina Varies (initial doses may range from 0.1 to 0.2 units/kg/d) Desired reduction can be achieved with appropriate dose and use of an insulin sensitizer when needed Hypoglycemia

Weight gain
  • Anti-diabetes drugs, salicylates, sulfonamide antibiotics, MAOIs, certain antidepressants, alcohol: potentiate hypoglycemia
  • β-blockers: mask symptoms of hypoglycemia
  • Nocturnal hypoglycemia less frequent with basal insulin compared to NPH
  • Renal impairment can increase risk of hypoglycemia
  • Preferred initial insulin type is basal (glargine, detemir, degludec)
  • Preferred prandial insulin is rapid-acting (lispro, aspart, glulisine)
Second-line oral agents
Second- generation sulfonylureasb Glyburide:

Conventional tablets: 2.5-5 mg once daily up to 10 mg twice daily

Micronized tablets: 1.5-3 mg once daily up to 6 mg twice daily

Glipizide:

Immediate release: 5-10 mg once or twice daily before meals up to 20 mg daily

Extended-release: 5-10 mg once daily up to 20 mg daily

Glimepiride:

1-2 mg once daily with first meal up to 8 mg once daily		 1.5%- 2% Hypoglycemia

Weight gain
  • Salicylates, NSAIDs, β-blockers, probenecid: potentiate hypoglycemic effects by displacing SUs from protein binding sites
  • β-blockers: mask symptoms of hypoglycemia
  • Fluoroquinolones, sulfonamide derivatives, MAOIs, hypoglycemic agents, cyclic antidepressants, fibric acid derivatives: potentiate hypoglycemic effects of SUs
  • CYP2C9 inhibitors/inducers: may increase/decrease SU concentrations
  • Glyburide is not preferred for use in the elderly or in patients with renal impairment. These populations experience more hypoglycemia since the parent drug and active metabolite are not eliminated as quickly
  • Lower initial doses of glipizide and glimepiride should be used in elderly patients and in patients with renal impairment
  • Efficacy of these agents may decrease with long-term use
Meglitinides Nateglinide:

60-120 mg 30 minutes before meals

Repaglinide:

0.5-1 mg 30 minutes before meals and increased weekly as needed to 4 mg before meals up to 16 mg daily		 0.8%- 1% Hypoglycemia (not as frequent as with SUs)

Weight gain
  • CYP2C8 inhibitors such as gemfibrozil, itraconazole, and trimethoprim and CYP3A4 inhibitors increase repaglinide concentrations
  • Salicylates, NSAIDs, β-blockers, MAOIs: potentiate hypoglycemic effects
  • CYP2C9 inhibitors: increase nateglinide concentrations
  • Used to reduce PPG
  • Glucose control is not improved when added to SU treatment
  • Use lower repaglinide dose with CrCl < 40 mL/min
  • Can be used for patients close to the A1C goal, patients with erratic meal schedules, or patients who experience hypoglycemia with SUs and renal insufficiency
Thiazolidinediones Pioglitazone: 15-30 mg once daily up to 45 mg once daily

Rosiglitazone: 4 mg daily given once or in divided doses up to 8 mg daily		 1%-1.5% Fluid retention

Peripheral edema

Weight gain

Fracture
  • Gemfibrozil: significantly increases pioglitazone concentrations; limit pioglitazone dose to 15 mg once daily
  • CYP2C8 inhibitors: increase TZD concentrations
  • CYP2C8 inducers: decrease TZD concentrations
  • Insulin: increased edema; reduce TZD dose if possible
  • Pioglitazone 15 mg dose should be started in patients with HF
  • In December 2015, the FDA removed the restriction on distribution and REMS for rosiglitazone as evidence does not indicate an increased risk of MI with rosiglitazone
  • Insulin and/or SU dose requirements may be reduced when using TZDs
  • Monitor closely in patients with hepatic impairment
  • Can cause or exacerbate HF; should not be used in patients with symptomatic HF
Alpha-glucosidase inhibitors Acarbose: 25 mg 3 times daily with the first bite of each meal up to 50 mg 3 times daily in patients < 60 kg and 100 mg 3 times daily in patients > 60 kg

Miglitol: 25 mg 3 times daily with the first bite of each meal up to 100 mg 3 times daily		 0.3%-1% Abdominal pain

Bloating

Diarrhea

Flatulence
  • Pancreatic enzymes, intestinal absorbents: reduce effect of α-glucosidase inhibitors; avoid concomitant use
  • Warfarin: effect may be increased by acarbose, monitor closely
  • Digoxin: concentration may be decreased by acarbose or miglitol; monitor digoxin concentrations
  • Propranolol, ranitidine: bioavailability may be reduced by miglitol
  • Used to reduce PPG
  • 25 mg once daily with a meal can be used as an initial dose of either agent to minimize abdominal symptoms
  • Dose titration should occur after 4 to 8 weeks or as tolerated
  • Acarbose is contraindicated in patients with cirrhosis
  • Both agents are not recommended in patients with serum creatinine > 2 g/dL or CrCl < 25 mL/min for miglitol
  • Use oral glucose if severe hypoglycemia occurs as other glycemic food sources will be affected by these agents
Dipeptidyl peptidase-4 inhibitors Sitagliptin: 100 mg once daily; 50 mg once daily with CrCl between 30 and 50 mL/min; 25 mg once daily with CrCl < 30 mL/min

Saxagliptin: 2.5 mg to 5 mg once daily; 2.5 mg once daily with CrCl < 50 mL/min and in hemodialysis

Alogliptin: 25 mg once daily; 12.5 mg once daily with CrCl between 30 and 60 mL/min; 6.25 mg once daily with CrCl < 30 mL/min or hemodialysis

Linagliptin: 5 mg once daily		 0.7%-1% Headache

Naso-pharyngitis
  • Digoxin, cyclosporine: concentrations of these agents are slightly increased by sitagliptin
  • CYP3A4/5 inhibitors: limit saxagliptin dose to 2.5 mg once daily
  • CYP3A4/5 inducers: decrease plasma concentrations of saxagliptin and linagliptin
  • P-glycoprotein inducers: may decrease efficacy of linagliptin
  • No significant interactions with alogliptin
  • All agents except linagliptin require dosage adjustment in moderate to severe renal impairment
  • Insulin and/or SU doses may need to be reduced
  • Alogliptin may increase hepatic enzymes
  • Use with caution in patients with existing HF
  • Pancreatitis and severe arthralgia have been reported with this class of agents
Sodium-glucose co-transporter 2 inhibitors Canagliflozin: 100 mg once daily before first meal up to 300 mg once daily; limit to 100 mg once daily with CrCl 45-60 mL/min

Dapagliflozin: 5 mg once daily up to 10 mg once daily

Empagliflozin:

10 mg once daily up to 25 mg once daily

Ertugliflozin: 5 mg once daily up to 15 mg once daily		 0.5%-1% Hypotension

Genital mycotic infections

Increased urination

Urinary tract infection

Hypoglycemia

Increased LDL cholesterol

Canagliflozin:

Hyperkalemia

Renal impairment
  • ACE inhibitors, ARBs, aliskiren, eplerenone, potassium-sparing diuretics: additive hyperkalemia and hypotension with canagliflozin
  • Primidone, phenobarbital, rifampin, ritonavir, phenytoin: decrease canagliflozin concentrations; increased canagliflozin dose may be required
  • Salicylates, SSRIs, MAOIs: increase hypoglycemic effects
  • Canagliflozin carries a boxed warning for risk of lower limb amputation in patients with type 2 DM and established CVD (or at risk for CVD)
  • Use cautiously in elderly patients with volume depletion due to increased risk of hypotension
  • Canagliflozin and ertugliflozin should not be used in patients with CrCl < 30 mL/min
  • Dapagliflozin should not be used in patients with CrCl < 60 mL/min
  • Empagliflozin should not be used in patients with CrCl < 45 mL/min
Second-line injectable agents
Glucagon-like peptide-1 receptor agonists Albiglutide:

30 mg SC once weekly with or without meals; can increase to 50 mg SC weekly

Dulaglutide:

0.75 mg SC once weekly with or without meals; can increase to 1.5 mg once weekly

Exenatide:

5 mcg SC twice daily within 1 hour before a meal; increased after 1 month to 10 mcg twice daily if needed.

Extended-release: 2 mg SC once every 7 days without regard to meals

Liraglutide:

0.6 mg SC once daily increased to 1.2 mg once daily after 1 week without regard to meals; increase to 1.8 mg once daily if needed

Lixisenatide: 10 mcg SC once daily within 1 hour before first meal of the day; increase to 20 mcg after 2 weeks

Semaglutide: 0.25 mg SC once weekly without regard to meals, increase to 0.5 mg once weekly after 1 month; may increase to 1 mg once weekly after 1 month, if needed		 0.9%-1.1% Nausea

Vomiting

Diarrhea

Weight loss
  • Oral pain medications and antibiotics: absorption may be delayed; administer these agents 1 hour before or 3 hours after GLP-1 receptor agonist
  • Warfarin: may increase INR and bleeding; monitor INR closely
  • Acetaminophen, digoxin, lovastatin: maximum concentrations lowered by exenatide
  • ACE inhibitors, NSAIDs, diuretics: worsened renal function with exenatide
  • Primary effect of exenatide is on PPG; other anti-diabetic agents should be used first to control FPG
  • Avoid exenatide in patients with severe renal impairment or history of pancreatitis
  • These agents carry a boxed warning regarding the risk of thyroid C-cell tumors and are contraindicated in patients with a personal or family history of medullary thyroid carcinoma
  • Liraglutide has a long duration of action and reduces both FPG and PPG
  • Initial dose of liraglutide is to minimize adverse events and is not expected to reduce glucose
  • Avoid use of these agents in patients with gastroparesis
  • Additive hypoglycemic effects occur when used with SUs and/or insulin; reduce dose of SU and/or insulin if glucose is close to normal
  • Exenatide should be refrigerated but can be stored at room temperature (< 77°F) for 28 to 30 days.
  • Liraglutide should be refrigerated prior to initial use but is stable for 30 days after first use at room temperature (< 86°F) or refrigeration
  • Albiglutide pens should be refrigerated but can be stored at room temperature (< 86°F) for up to 4 weeks. Should be used within 8 hours of reconstitution
  • Dulaglutide and lixisenatide should be refrigerated but can be stored at room temperature (< 86°F) for up to 14 days
  • Semaglutide should be refrigerated but can be stored at room temperature (< 86°F) for up to 56 days
Amylin mimetics Pramlintide:

Type 2 DM:

60 mcg SC prior to meals titrated up to 120 mcg if needed

Type 1 DM:

15 mcg SC prior to meals titrated up to 60 mcg if needed		 0.6% Nausea

Hypoglycemia (can be severe)
  • Oral pain medications, antibiotics, and oral contraceptives: absorption may be delayed; administer these agents 1 hour before or 2 hours after pramlintide
  • Administer only to patients receiving insulin (type 1 or type 2)
  • Mainly used to reduce PPG
  • Reduce rapid-acting insulin dose by 30% to 50% when starting pramlintide
  • Reduction in basal insulin may also be necessary
  • Pramlintide is stable for 30 days after first use at room temperature (< 86°F) or refrigeration
a Should be used first-line in patients with severe hyperglycemic symptoms and/or with glucose ≥ 300 mg/dL or A1C > 10% according to ADA or A1C ≥ 9% with symptoms according to AACE.
b First-generation sulfonylureas (chlorpropamide, tolbutamide, and tolazamide) are rarely used due to their long duration of action, severe hypoglycemic and hyponatremic effects.

Abbreviations: A1C, glycosylated hemoglobin; ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; CrCl, creatinine clearance; CVD, cardiovascular disease; CYP, cytochrome P450; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; FDA, Food and Drug Administration; FPG, fasting plasma glucose; GLP-1, glucagon-like peptide-1; HF, heart failure; INR, international normalized ratio; MAOI, monoamine oxidase inhibitor; MI, myocardial infarction; NSAID, nonsteroidal anti-inflammatory drug; PPG, postprandial glucose; REMS, risk evaluation and mitigation strategy; SSRI, selective serotonin reuptake inhibitor; SC, subcutaneous; SU, sulfonylurea; TZD, thiazolidinedione.
Table 2. Characteristics of Various Insulin Types8,18-28
Generic/ brand name Onset(min) Peak Duration(h) Timing of dose Dosage forms available Stability (days)a
Unopened In-use
Room temperatureb Refrigerationc Room temperatureb
Rapid-acting
Aspart (Novolog, Fiasp) 10-20 Novolog:
40-50 min

Fiasp: 63 min		 Novolog:3-5

Fiasp: 5-7		 Novolog: 5-10 min before meal

Fiasp: At the start of a meal to 20 min after the start of a meal		 Vial, cartridge, pen 28 Novolog vial, Fiasp vial, pen: 28 Vial, cart-ridge, pen: 28
Glulisine (Apidra) 25 45-48 min 4-5.3 Between 15 min before and 20 min after meal Vial, pen 28 Vial: 28 Vial/ pen: 28
Lispro (Humalog, Admelog) 15- 30 30-150 min 3-6.5 Between 15 min before and immediately after meal Vial, cartridge, pen 28 Vial: 28 Vial/ cart-ridge, pen: 28
Short-acting
Regular (Humulin R, Novolin R) 30-60 1-5 h 6-10 30 min before meal Novolin R: vial, pen

Humulin R: vial		 Novolin R vial: 42

Novolin R pen: 28

Humulin R: 31		 Humulin R: 31 Novolin R: vial: 42

Novolin R pen: 28

Humulin R: 31
Regular (Afrezza) 15-30 1-2 h 2.6 At the beginning of a meal Single-use inhalation cartridge 10 Blister card or strip should not be refrigerated once opened 3
Intermediate-acting
NPH (Humulin N,
Novolin N)		 60-120 4-14 h Up to 24 Morning and/or bedtime Vial, pen Novolin N vial: 42

Novolin N pen: 28

Humulin N vial: 31

Humulin N pen: 14		 Humulin N vial: 31 Novolin N vial: 42

Novolin N pen: 28

Humulin N vial: 31

Humulin N pen: 14
NPH/regular
(Humulin 70/30, Novolin 70/30)		 30 1.5-16 h Up to 24 30-60 min before a meal Novolin 70/30: vial

Humulin 70/30: vial, pen		 Novolin 70/30: 42

Humulin 70/30 vial: 31

Humulin 70/30 pen: 10		 Humulin 70/30 vial: 31 Novolin 70/30: 42

Humulin 70/30 vial: 31

Humulin 70/30 pen: 10
Isophane/ lispro (Humalog 75/25, Humalog 50/50) 15-30 1-6.5 h Up to 24 Within 15 min before a meal Vial, pen Vial: 28

Pen: 10		 Vial: 28 Vial: 28

Pen: 10
Isophane/aspart (Novolog 70/30 Mix) 10-20 1-4 h Up to 24 Between 15 min before and after a meal Vial, pen Vial: 28

Pen: 14		 Vial: 28 Vial: 28

Pen: 14
Long-acting
Detemir (Levemir) 60-120 No peak 7.5 to > 24 Morning and/or evening Vial, pen Vial, pen: 42 Vial: 42 Vial, pen: 42
Glargine U-100 (Lantus, Basaglar) 60 No peak 10 to > 24 Morning or evening Vial, pen Vial, pen: 28 Vial: 28 Vial, pen: 28
Glargine U-300
(Toujeo)		 Over 360 No peak > 24 Morning or evening Pen 56 Should not be refrigerated 56
Ultra-long acting
Degludec
(Tresiba)		 30- 90 12 42 Morning or evening Pen 56 Should not be refrigerated 56
a Unopened insulin products stored at refrigeration are stable until the manufacturer’s expiration date.
b Room temperature is defined as temperature below 86°F for most products and below 77°F for Novolin products in a vial.
c Refrigeration is defined as temperature between 36°F to 46°F; in-use insulin cartridges, pens and Novolin products should not be refrigerated.

THYROID DISORDERS

Overview

The American Thyroid Association (ATA) estimates that over 12% of people in the United States will develop a thyroid condition in their lifetime.29 Women are up to 8 times more likely to have thyroid-related conditions than men.

The primary function of the thyroid in adults is to maintain metabolic homeostasis. Nearly every system in the human body requires thyroid hormone for proper function.30,31 Thyroid disorders can be categorized into abnormal function or structure of the thyroid, but structural disorders, such as nodules, may not affect thyroid function. Therefore, thyroid disorders are more commonly categorized as those that result in excess thyroid hormone, hyperthyroidism, or those in which thyroid hormone is lacking, hypothyroidism. Thyrotoxicosis results when the body is exposed to excess thyroid hormone.

Graves’ hyperthyroidism is the most common cause of hyperthyroidism in the United States while Hashimoto’s thyroiditis and iatrogenic causes are the most common etiologies of hypothyroidism.32,33 Thyroiditis, inflammation of the thyroid gland, initially leads to excess thyroid hormone release, which is followed by a hypothyroid period. A summary of the primary causes of hypothyroidism and hyperthyroidism is provided in Table 3.

Table 3. Causes of Hypothyroidism and Hyperthyroidism30-33
Hypothyroidism Hyperthyroidism
Hashimoto’s or atrophic thyroiditis Graves’ disease
Silent thyroiditis (includes postpartum) Toxic multinodular goiter or toxic adenoma
Congenital hypothyroidism Thyroiditis
Iatrogenic hypothyroidism caused by surgical removal of the thyroid, radiation to the thyroid, or drug-induced hypothyroidism Excess synthetic thyroid hormone
Iodine deficiency Excess iodine consumption

The thyroid follicles are responsible for production of thyroxine (T4).30 The thyroid also produces some triiodothyronine (T3), but the majority of T3 is produced upon conversion of T4 in the peripheral tissues. Thyroid hormones are heavily bound to proteins in the bloodstream including thyroxine-binding globulin, albumin, and transthyretin, but it is unbound hormones that control secretion of thyroid-stimulating hormone (TSH) from the pituitary. Thyrotropin-releasing hormone (TRH) also functions to control TSH secretion. The final component required to maintain euthyroidism is the conversion of T4 to T3, which can be affected by a variety of factors.

The signs and symptoms of hyperthyroidism (thyrotoxicosis) and hypothyroidism are summarized in Table 4.

Table 4. Signs and Symptoms of Thyroid Disorders30-33
Hypothyroidism Hyperthyroidism
  • Fatigue
  • Weight gain
  • Cold intolerance
  • Constipation
  • Dry skin
  • Depression
  • Muscle pain or stiffness
  • Menorrhagia or infertility in women
  • Hyperactivity, nervousness, or irritability
  • Heat intolerance
  • Tremors
  • Palpitations, rapid and irregular heartbeat
  • Diarrhea
  • Weight loss
  • Goiter
  • Weakness
  • Warm, moist skin

A number of laboratory and diagnostic tests are used in conjunction with symptoms and physical examination to diagnose thyroid disorders. These are briefly summarized in Table 5.

Table 5. Common Laboratory and Diagnostic Tests for Thyroid Disorders30,31
Laboratory parameter Comments
Serum TSH Generally elevated with hypothyroidism (although TSH may be low or normal depending on the cause of hypothyroidism) and low with hyperthyroidism
Free serum T3 and T4 Generally low with hypothyroidism and elevated with hyperthyroidism
TPO, Tg, or TSI antibodies Presence signals an autoimmune cause of thyroid dysfunction
Radioactive iodine uptake Measures the amount of iodine the thyroid is taking from the blood
Thyroid scan Shows distribution of iodine in the thyroid gland
Abbreviations: T4, thyroxine; T3, triiodothyronine; Tg, thyroglobulin; TPO, thyroid peroxidase; TSH, thyroid-stimulating hormone; TSI, thyroid-stimulating immunoglobulin.

Treatment and Monitoring

The ATA and AACE have developed comprehensive clinical practice guidelines on hypothyroidism.34 The ATA has also published a more recent focused guideline specific to thyroid hormone replacement in patients with hypothyroidism.35 In 2016, the ATA also published an updated guideline on the treatment of hyperthyroidism.36 Overall treatment goal of both disease states is to maintain euthyroidism and minimize the symptoms that result from hyper- or hypothyroidism.

Hypothyroidism

All patients with primary hypothyroidism and a TSH > 10 mIU/L should be treated.34 Some patients with TSH levels between 4.5 and 10 mIU/L should also be treated, but there is not a firm consensus on which of these patients requires treatment. The recommended treatment for hypothyroidism is synthetic L-thyroxine (T4) sodium (levothyroxine).34,35 Initial dosing of L-thyroxine is approximately 1.6 mcg/kg (based on ideal body weight) when there is little residual thyroid function. Patients with no thyroid function may require higher doses while those with subclinical hypothyroidism may require less. Notably, the ATA/AACE guidelines advocate that patients be consistently maintained on a particular formulation of L-thyroxine during treatment.34 For optimal absorption, L-thyroxine should be administered once daily either 30 to 60 minutes prior to breakfast or at bedtime at least 4 hours after the last meal.

According to the ATA/AACE, the addition of T3 (liothyronine) to L-thyroxine is not supported by evidence and is therefore not recommended.34 In addition, desiccated animal thyroid, which is a combination of T3 and T4, is not recommended.

A TSH level should be obtained 4 to 6 weeks after treatment initiation or dose change.34 Dosage changes of 12.5-25 mcg/d are usually made but these increments may be smaller as the TSH goal is approached.34,35 Optimal TSH levels are determined by the particular laboratory assay; however, a general reference range is 0.4 to 4.0 mIU/L. Pregnant patients will require dosage adjustment and TSH levels should be maintained at < 2.5 mIU/L for the first trimester and < 3.0 in the second and third trimesters.35 Once stable, TSH levels can be monitored at 4 to 6 months then annually. For patients with hypothalamic or pituitary failure, serum T4 rather than TSH must be used for monitoring therapy.30

There are few adverse reactions to L-thyroxine when used at appropriate doses. Excess L-thyroxine can result in cardiac toxicity or reduced bone density. Animal-derived products may cause allergic reactions, but this is rare with synthetic thyroid replacement.30 A number of drug interactions occur due to interference with L-thyroxine absorption (eg, drugs affecting gastrointestinal [GI] pH, calcium, iron). In addition, some drugs have an effect on the thyroid gland, the hypothalamic-pituitary axis, or affect the clearance or metabolism of L-thyroxine, thus resulting in additional drug interactions.34

Hyperthyroidism

The treatment of hyperthyroidism is based on the underlying etiology. There are 3 basic treatment options for patients with Graves’ hyperthyroidism: antithyroid drugs, thyroidectomy, or radioactive iodine.30 Patients with toxic multinodular goiter or toxic adenoma are typically managed with radioactive iodine or thyroidectomy; antithyroid drugs are rarely used.36 A summary of the treatment options for Graves’ hyperthyroidism is provided in Table 6.

Table 6. Treatment Options for Graves’ Hyperthyroidism30,36
  Patient characteristics favoring selection Contraindications Comments

Thyroidectomy

Large goiter

Low uptake of radioactive iodine

Suspected thyroid malignancy

Concomitant hyperparathyroidism requiring surgery

Females planning pregnancy in less than 6 months

Comorbidities (cardiopulmonary, cancer)

Pregnancy (relative contraindication; safest in second trimester)

Permanent hypothyroidism requiring L-thyroxine will result

Potassium iodide is administered perioperatively

Radioactive iodine (131I)

Future pregnancy

Surgical or anti-thyroid drug contraindications

Pregnancy (current or planning within 4 to 6 months)

Lactation

Thyroid cancer

Unable to comply with radiation safety guidelines

Typically results in permanent hypothyroidism

Obtain pregnancy test within 48 hours of treatment initiation

Antithyroid medications

Patients with high likelihood of remission

Elderly

Previous neck surgery or irradiation

Pregnancy

Previous reaction to antithyroid drugs

MMI is the first-line agent; PTU is second-line

Generally the initial treatment in severe hyperthyroidism or in preparation for thyroidectomy or radioactive iodine

Low cure rate
Abbreviations: MMI, methimazole; PTU, propylthiouracil.

Methimazole and propylthiouracil are the currently available antithyroid medications (see Table 7).36 Methimazole is the preferred option with the exception of the first trimester of pregnancy or thyroid storm when propylthiouracil is preferred. Generally, the antithyroid drugs do not induce remission but are effective in maintaining euthyroid. Antithyroid drugs are typically continued for 12 to 18 months, then tapered or discontinued if TSH is normal. Approximately 20% to 30% of patients remain in remission, but those who again develop hyperthyroidism are generally treated with radioactive iodine or thyroidectomy rather than another course of medication therapy.

Beta-blockers are often used in hyperthyroid patients to control heart rate, BP, muscle weakness, and tremor.30

Table 7. Antithyroid Medications30,36
Medication Dosage form Initial dosage Maintenance dosage Adverse reactions Monitoring Comments

MMI

5 and 10 mg tablets

10-30 mg/d; may be given once daily or divided doses

5-10 mg/d

Arthralgias

Fever

Pruritic rash

Transient leukopenia

Agranulo-cytosisa

Hepato-toxicitya

Free T4 every 4 weeks until euthyroid then every 2 to 3 months

WBC if febrile illness or pharyngitis

LFTs in patients taking PTU who develop rash, jaundice, dark urine, joint or abdominal pain, nausea, or fatigue

Serum TSH is not an accurate monitoring parameter early in therapy as it may remain suppressed for several months

PTU should be discontinued if LFTs exceed 3 times ULN or if initially elevated LFTs continue to increase (MMI may be used)

PTU

50 mg tablets

50-150 mg 3 times daily

50 mg 2 or 3 times daily
a More commonly reported with PTU.
Abbreviations: LFT, liver function test; MMI, methimazole; PTU, propylthiouracil; T4, thyroxine; TSH, thyroid-stimulating hormone; ULN, upper limit of normal; WBC, white blood cell.

Patient Case:

MR is a 32-year-old Hispanic-American female with a medical history significant for hypertension, hypothyroidism, and smoking. Her family history is significant for a mother with type 2 DM and father with a history of myocardial infarction (MI). Her current medications are Ortho-Tri-Cyclen once daily, hydrochlorothiazide (HCTZ) 25 mg once daily, diltiazem ER 120 mg once daily, and levothyroxine 0.125 mg once daily. She presents to clinic today for a routine follow-up. She works day shifts at the local grocery store with occasional evening or weekend shifts. Her prescription benefits are limited, and she prefers to use only generic medications. She does no regular physical activity and reports eating fast food for dinner. She complains of headache, fatigue, and increased thirst. Physical exam reveals the following: BP 130/80 mm Hg, heart rate 65 beats per minute, weight 170 pounds, height 64 inches. Pertinent laboratory findings include: FPG 165 mg/dL, A1C 8.5%, serum creatinine (SCr) 1.2 mg/dL, serum potassium 4.1 mg/dL, normal liver function, and thyroid stimulating hormone (TSH) 0.3 mIU/L. Her estimated glomerular filtration rate (eGFR) is 60 mL/min.

What are MR’s risk factors for type 2 DM?

Race, family history, hypertension, overweight, and physical inactivity.

Which of MR’s medications can cause hyperglycemia?

Thyroid medications, diuretics, and oral contraceptives can contribute to hyperglycemia.

After repeat testing, MR is diagnosed with type 2 DM. What is the best treatment option for initial management?

Considering MR’s A1C, both nonpharmacologic and pharmacologic interventions should be implemented. Since her eGFR is greater than 45 mL/min and she does not have other contraindications, metformin is the best treatment option. Initiate 500 mg twice daily. Counsel on potential GI symptoms and recommend taking with food to minimize GI upset. Also provide recommendations for dietary changes and physical activity. Counsel on SMBG and have her check FPG 2 to 3 times per week. Follow-up via telephone in 1 month to assess adherence to changes and FPG values. Increase metformin dose if needed and recheck A1C in 3 months.

What approach should be taken to manage MR’s BP?

Although MR’s BP meets the goal, MR is not receiving an ACE inhibitor or ARB. Diltiazem should be switched to an ACE inhibitor that is available as a generic, such as lisinopril. MR’s BP should be rechecked in 1 month along with SCr and potassium.

What other parameters should be evaluated to optimize MR’s health?

Considering her family history, smoking, and new-onset type 2 DM, MR should be evaluated for ASCVD risk. Her LDL should be checked, and a statin should be initiated if needed. Based on her risk factors, her LDL goal should be < 70 mg/dL (according to the AACE guidelines). Additionally, the need for antiplatelet therapy should be assessed by determining her 10-year CVD risk. Smoking cessation should be addressed, and MR should be referred to a program if she expresses the desire to quit. MR should have an ophthalmic exam, foot exam, and a urine albumin screen. Other symptoms of neuropathy should also be evaluated.

How should MR’s thyroid disorder be managed?

Although MR has a history of hypothyroidism, her TSH level is low. This suggests hyperthyroidism induced by levothyroxine. The dose of levothyroxine should be lowered and TSH rechecked in 4 to 6 weeks.

ADRENAL DISORDERS

Overview

The adrenal cortex produces 3 categories of hormones: glucocorticoids (eg, cortisol), mineralocorticoids (eg, aldosterone), and androgen precursors (eg, dehydroepiandrosterone).37,38 Two primary disorders result from overproduction of hormones in the adrenal cortex: Cushing’s syndrome results from excess cortisol and hyperaldosteronism results from excess aldosterone production. Underproduction of adrenal hormones can also result in medical disorders, most commonly Addison’s disease.

Cushing’s Syndrome

Cushing’s syndrome is a rare disorder with an incidence of 1 or 2 cases per 100,000 people per year that results from excess exposure to glucocorticoids.37 It is generally categorized as adrenocorticotropic hormone (ACTH)-dependent or ACTH-independent. 37,38 ACTH is a hormone released from the pituitary gland that regulates cortisol synthesis. ACTH-dependent Cushing’s syndrome is more common than other forms. Cushing’s disease refers specifically to Cushing’s syndrome that is caused by a pituitary adenoma. Interestingly, the most common cause of Cushing’s syndrome is iatrogenic, caused by therapeutic use of glucocorticoids (this is also known as exogenous Cushing’s syndrome).

Almost all patients present with central obesity and facial rounding. 37,38 Other common presenting symptoms include hypertension, glucose intolerance, dyslipidemia, myopathies, and muscle weakness. The first step in the diagnostic strategy of Cushing’s syndrome is to establish the presence of excess cortisol. Secondly, the etiology of the syndrome must be identified for proper treatment. Patients with Cushing’s syndrome have a poor prognosis if left untreated with a 5-year survival rate of only 50%.39

When a tumor is the primary cause of the Cushing’s syndrome, surgical removal of the tumors as well as radiotherapy for some tumor types is indicated. Pharmacotherapy may be used perioperatively or in patients who are not surgical candidates. 37,38  These medications work by a variety of mechanisms including reduction of ACTH secretion, inhibition of cortisol development, adrenolysis, or via blocking the glucocorticoid receptor.37,40 A summary of the treatment options is provided in Table 8. A combination of agents may be more effective or better tolerated than use of a single agent.

Table 8. Pharmacotherapy of Cushing’s Syndrome7,37,40-45
Medication MOA Dosage Adverse Reactions Monitoring Comments

Cabergoline

Reduces ACTH secretion

1-2 mg/wk

Nausea

Hypotension

Heart valve disorders

Pulmonary fibrosis

Echocardiogram

Chest x-ray

Limited efficacy; low sustained response rate of 30%-40%

Etomidate

Blocks cortisol development

Initial IV dose of 0.04-0.05 mg/kg/h with dose titration based on serum cortisol

Injection site reactions

Transient skeletal muscle movements

Requires ICU monitoring

Used in severe or life-threatening cases

Ketoconazole

Blocks cortisol development

Initial dose of 200 mg once or twice daily; maintenance dose of 200-1200 mg/d divided twice daily

Gynecomastia

Hypogonadism

GI upset

Elevated LFTs

Hepatotoxicity (rare)

LFTs

Several weeks of therapy are required before beneficial effects are seen

Numerous drug interactions (CYP3A4 substrate and inhibitor)

Metyrapone

Blocks cortisol development

Initial dose of 0.5-1 g/d divided every 4-6 hours; maintenance dose of 1-2 g/d divided every 4-6 hours

Androgenic (hirsutism, acne)

Electrolyte abnormalities

HTN

N/V

Allergic rash

BP

Electrolytes

Numerous drug interactions (CYP3A4 inducer)

Mifepristone

Glucocorti-coid receptor blocker

Initial dose of 300 mg/d increased by 300 mg/d every 2-4 weeks; maintenance dose of 600-1200 mg/d

Fatigue

Nausea

Headache

Arthralgia

Edema

Hypokalemia

Potassium

Pregnancy test

Pelvic ultrasound to monitor for endometrial hyperplasia

Must be avoided in pregnancy

Multiple drug interactions (CYP3A4 inducer and inhibitor, also CYP2C8/2C9 and CYP2B6 interactions)

Mitotane

Adrenolytic (atrophies the adrenal cortex)

Initial dose of 500 mg three times daily; titrate as needed to 3000 mg three times daily

Neurologic (ataxia, confusion, lethargy)

Nausea

Diarrhea

Potassium

UFC

Urinary steroid production

Weeks to months before beneficial effects are seen

Stored in adipose tissue for years after discontinuation (avoid in women desiring pregnancy)

GI effects are minimized if administered with food

Pasireotide

Reduces ACTH secretion

0.3-0.9 mg SC twice daily

GI

Hyperglycemia

Blood glucose

  
Abbreviations: ACTH, adrenocorticotropic hormone; BP, blood pressure; CNS, central nervous system; CYP, cytochrome P450; FDA, Food and Drug Administration; GI, gastrointestinal; HTN, hypertension; LFTs, liver function tests; ICU, intensive care unit; IV, intravenous; MOA, mechanism of action; N/V, nausea and vomiting; SC, subcutaneous; UFC, urinary free cortisol.

Hyperaldosteronism

Primary aldosteronism (PA) is a collection of disorders that result in increased aldosterone production, which can lead to hypertension, cardiovascular complications, sodium retention, and hypokalemia.46 Recent studies indicate that PA is present in more than 10% of patients who have hypertension. There are a number of causes of PA, but bilateral adrenal hyperplasia is the most common cause (65%) followed by aldosterone-producing adenoma (30%).38 The Endocrine Society recommends screening of patients using the plasma aldosterone-renin ratio (ARR) upon presentation with: BP > 150/100 mm Hg; treatment-resistant hypertension; hypertension with concomitant hypokalemia; hypertension with adrenal incidentaloma; hypertension with sleep apnea; hypertension with a family history of early-onset hypertension or stroke; or those with first-degree relatives with PA.46 Further diagnostic tests are required to determine the underlying etiology of the PA.

The primary therapy for aldosterone-producing adenomas is surgical resection; however, those with bilateral adrenal hyperplasia are medically managed. Spironolactone is the recommended treatment, but other aldosterone antagonists may be used. A summary of the available treatment options for bilateral adrenal hyperplasia is provided in Table 9.

Table 9. Pharmacotherapy of Primary Aldosteronism38,46
Medication Initial dose Dosage range Adverse reactions Monitoring Comments

Amiloride

5 mg twice daily

20 mg/d divided in 2 doses

GI

Hyperkalemia

Hypotension

Headache

SCr

BP

Potassium

Less effective than spironolactone

Eplerenone

50 mg daily

100-300 mg/d (titrate at 1-2 month intervals)

Hyperkalemia

Hypotension

Headache

CYP3A4 substrate; drug interaction with CYP3A4 inhibitors

Fewer endocrine (eg, gynecomastia) adverse effects than spironolactone

Spironolactone

25 mg daily

100-400 mg/d (titrate at 1-2 month intervals)

GI

Gynecomastia

Impotence

Hyperkalemia

Hypotension

  
Abbreviations: BP, blood pressure; CYP, cytochrome P450; GI, gastrointestinal; PA, primary aldosteronism; SCr, serum creatinine.

Adrenal Insufficiency

Primary adrenal insufficiency, also known as Addison’s disease, is a rare condition with a prevalence of 10 to 15 cases per 100,000 people.47 The most common cause of primary adrenal insufficiency in the United States is autoimmune dysfunction resulting in adrenal cortex dysfunction.38 Deficiencies of the adrenal hormones result in symptoms of weakness, weight loss, salt craving, dizziness, and GI complaints. Generally, the short cosyntropin stimulation test to detect hypocortisolism is used for diagnosis.

Treatment of Addison’s disease consists of glucocorticoid and mineralocorticoid replacement. To simulate normal diurnal cortisol production, glucocorticoids are generally given twice daily with two-thirds of the dose in the morning and one-third of the dose approximately 6 to 8 hours later.38,48 The Endocrine Society recommends hydrocortisone (at a dose of 15-25 mg/d) or cortisone acetate (at a dose of 20-35 mg/d).49 Prednisolone (3-5 mg/d) is an alternative treatment option. Importantly, additional glucocorticoid supplementation must be provided during stressful situations and illness. Symptomatic monitoring should be performed every 6 to 8 weeks with the dosage adjusted accordingly.38,46Table 10 describes symptoms of over- or under-replacement; patients should be carefully questioned about these symptoms at every follow-up appointment. Many patients will also require mineralocorticoid supplementation with fludrocortisone 0.05-2 mg/d. Supplementation with dehydroepiandrosterone (DHEA), a dietary supplement, is not recommended for all patients but may improve mood and energy in some patients.

Table 10. Symptomatic Monitoring for Primary Adrenal Insufficiency47,48
Over-replacement Under-replacement
  • Weight gain
  • Insomnia
  • Peripheral edema
  • Weight loss
  • Nausea
  • Decreased appetite
  • Lethargy

Focus Points for Medication Therapy Management in Endocrine Disorders

Medication therapy management (MTM) should initially include a thorough patient medication history (including prior agents prescribed), appropriateness of current dosage regimens, any adverse effects, potential drug interactions, adherence issues, patient preferences (including the preferred communication method), and cost considerations.50,51

Type 2 DM

  • Determine glycemic goals based on age, comorbidities, extent of diabetes complications, duration of diabetes, life expectancy; usual A1C goal < 7% or < 6.5% if tolerated
  • Choose treatment based on patient comorbidities, efficacy, and adverse events; use metformin first-line if not contraindicated; use insulin initially in patients with severe hyperglycemic symptoms and A1C > 9%; avoid TZDs and use DPP-4 inhibitors with caution in patients with HF
  • When considering dual therapy after initiation of metformin, patients with established CKD, HF, or ASCVD should preferentially receive a GLP-1 receptor agonist or SGLT2 inhibitor with demonstrated risk reduction for their specific comorbidity
  • Monitor adherence to lifestyle interventions and medications; recognize/address barriers
  • Monitor adverse events, especially hypoglycemia, and drug interactions; adjust medication accordingly (see Table 1)
  • Monitor blood glucose and A1C; assess need for dual or triple therapy with additional oral agents or insulin based on degree of control needed; if parameters are close to goal, evaluate need for agents that reduce PPG
  • Ensure appropriate monitoring and management of BP, lipids, antiplatelet use, ophthalmic exam, foot exam, urine albumin screen
  • When using medications with common adverse events, explain expected symptoms and methods to reduce events
  • When using medications that cause hypoglycemia, explain expected symptoms and management of varying degrees of hypoglycemia as well as methods to reduce future occurrences; in patients receiving insulin, provision of glucagon and caregiver training on use may be necessary; provide means for quick communication if symptoms are intolerable
  • Educate on SMBG or CGM technique and timing; assist in glucose monitor selection (may be based on patient’s insurance formulary); demonstrate blood glucose monitoring technique and verify patient’s technique; educate on timing and documentation of self-monitoring
  • Counsel on using, storing, and self-injection technique of injectable agents including insulin; determine appropriate dosage form (insulin needle, refillable pen, disposable pen) based on ease of use and patient preference; educate on onset of action and timing in relation to meals; demonstrate injection or inhalation technique and verify patient’s technique; educate on appropriate order of insulin use when mixing 2 types of insulin
  • Ensure patient understanding of parameters used in monitoring; remind patients that the A1C measures the average glucose over the past 3 months

Thyroid Disorders

  • For patients with hypothyroidism, determine degree of hypothyroidism as well as patient symptoms to assess need for treatment; use synthetic L-thyroxine preparation and ensure formulation consistency over time
  • For patients with Graves’ hyperthyroidism, identify patients that are candidates for antithyroid medications; use methimazole for nonpregnant patients; propylthiouracil is reserved for pregnant patients or in cases of thyroid storm
  • For hypothyroid patients, recheck TSH 4 to 6 weeks after treatment initiation; adjust dose as need in 12.5 to 25 mcg increments
  • For hyperthyroid patients, initially check T4 levels every 4 weeks until normal; re-evaluate need to continue treatment after 12 to 18 months
  • Assess for symptom resolution and need for additional treatment to manage symptoms
  • L-thyroxine should be taken on an empty stomach; counsel on timing of other medications to avoid drug interactions
  • Discuss likelihood of achieving remission and duration of treatment in patients with Grave’s disease

Adrenal Disorders

  • The treatment of adrenal disorders is dependent on the underlying etiology
  • Patients with adrenal insufficiency (generally Addison’s disease) require glucocorticoid supplementation, while the primary treatment of Cushing’s syndrome is surgical management, and aldosterone antagonists such as spironolactone are the mainstay of treatment for patients with PA
  • Patients with Addison’s disease must be carefully monitored for over- or under-supplementation of glucocorticoids
  • Patients receiving pharmacologic treatment for PA should have SCr, potassium, and BP monitored regularly
  • Patients with Addison’s disease should be counseled on supplementation of glucocorticoids during times of stress
  • Patients with Addison’s disease should wear medical alert bracelets to inform health care providers of the need for corticosteroid supplementation in times of emergency
  • Patients receiving pharmacologic treatment for PA should be counseled on symptoms of hypotension

References

  1. Centers for Disease Control and Prevention. National Diabetes Statistics Report: National estimates of diabetes and its burden in the United States, 2017. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2017.
  2. Powers AC, D’Alessio D. Endocrine pancreas and pharmacotherapy of diabetes mellitus and hypoglycemia. In: Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 13th ed. New York, NY: McGraw-Hill; 2018. http://accesspharmacy.mhmedical.com/content.aspx?bookid=2189&sectionid=172482821. Accessed April 17, 2019.
  3. Triplitt CL, Repas T, Alvarez C. Diabetes mellitus. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L, eds. Pharmacotherapy: A Pathophysiologic Approach. 10th ed. New York, NY: McGraw-Hill; 2017. http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861&sectionid=146065891. Accessed April 17, 2019.
  4. American Diabetes Association. Standards of medical care in diabetes—2019. Diabetes Care. 2019;42(Suppl 1):S1-S193.
  5. American Association of Clinical Endocrinologists. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 DM management algorithm- 2019 executive summary. Endocr Pract. 2019;25(1):69-100.
  6. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 DM, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669-2701.
  7. Wickersham RM, ed. Drug Facts and Comparisons. St. Louis, MO: Wolters Kluwer Health; 2019. http://onlinefactsandcomparisons.com. Accessed May 3, 2019. 
  8. Freeman JS, Gross B. Potential drug interactions associated with treatments for type 2 DM and its comorbidities: a clinical pharmacology review. Expert Rev Clin Pharmacol. 2012;5(1):31-42.
  9. International Society for Pediatric and Adolescent Diabetes. ISPAD clinical practice consensus guidelines 2018: type 2 DM mellitus in youth. Pediatr Diabetes. 2018;19(Suppl 27):28-46.
  10. Copeland KC, Silverstein J, Moore KR, et al. Management of newly diagnosed type 2 DM mellitus (T2DM) in children and adolescents. Pediatrics. 2013;131(2):364-382.
  11. The Medical Letter. Drugs for type 2 DM. Med Lett Drugs Ther. 2017;59(1512):9-18.
  12. Scheen AJ. Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 DM mellitus. Drugs. 2015;75(1):33-59.
  13. Nauck M. Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab. 2016;18(3):203-216.
  14. Food and Drug Administration. FDA drug safety communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. http://www.fda.gov/drugs/drugsafety/ucm493244.htm. Updated April 8, 2016. Accessed May 8, 2019.
  15. Food and Drug Administration. FDA drug safety communication: FDA eliminates the risk evaluation and mitigation strategy (REMS) for rosiglitazone-containing diabetes medicines. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-eliminates-risk-evaluation-and-mitigation-strategy-rems. Updated December 16, 2015. Accessed May 8, 2019.
  16. Drugs for type 2 DM. Pharmacist’s Letter/Prescriber’s Letter. Clinical resource #330711. July 2017.
  17. Comparison of GLP-1 agonists. Pharmacist’s Letter/Prescriber’s Letter. Clinical Resource #330104. January 2017.
  18. Comparison of insulins. Pharmacist’s Letter/Prescriber’s Letter. Clinical Resource #331203. December 2017.
  19. Novolin N [package insert]. Plainsboro, NJ: Novo Nordisk; 2018.
  20. Humulin N [package insert]. Indianapolis, IN: Eli Lilly and Company; 2018.
  21. Novolin 70/30 [package insert]. Plainsboro, NJ: Novo Nordisk; 2018.
  22. Humulin 70/30 [package insert]. Indianapolis, IN: Eli Lilly and Company; 2018.
  23. Lantus [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2018.
  24. Basaglar [package insert]. Indianapolis, IN: Eli Lilly and Company; 2018.
  25. Levemir [package insert]. Plainsboro, NJ: Novo Nordisk; 2019.
  26. Toujeo [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2019.
  27. Tresiba [package insert]. Plainsboro, NJ: Novo Nordisk; 2018. 
  28. Afrezza [package insert]. Danbury, CT: Mannkind Corp; 2018.
  29. Prevalence and impact of thyroid disease. American Thyroid Association website. https://www.thyroid.org/media-main/press-room/. Accessed May 8, 2019.
  30. Jonklaas J, Kane MP. Thyroid disorders. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L, eds. Pharmacotherapy: A Pathophysiologic Approach. 10th ed.New York, NY: McGraw-Hill; 2017. http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861&sectionid=146066204. Accessed May 8, 2019.
  31. Esfandiari NH, McPhee SJ. Thyroid disease. In: Hammer GD, McPhee SJ, eds. Pathophysiology of Disease: An Introduction to Clinical Medicine. 8th ed. New York, NY: McGraw Hill; 2019. http://accesspharmacy.mhmedical.com/content.aspx?bookid=2468&sectionid=198224090. Accessed May 8, 2019.
  32. Hyperthyroidism. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). https://www.niddk.nih.gov/health-information/endocrine-diseases/hyperthyroidism. Updated August 2016. Accessed May 8, 2019.
  33. Hypothyroidism. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). https://www.niddk.nih.gov/health-information/endocrine-diseases/hypothyroidism. Updated August 2016. Accessed May 8, 2019.
  34. Garber JR, Cobin RH, Gharib H, et al; American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012;19(6):989-1028.
  35. Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism. Thyroid. 2014;24(12):1670-1751.
  36. Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid. 2016;26(10):1343-1421.
  37. Arlt W. Disorders of the adrenal cortex. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 20th ed.New York, NY: McGraw-Hill; 2018. http://accesspharmacy.mhmedical.com/content.aspx?bookid=2129&sectionid=192287137. Accessed May 16, 2019.
  38.  Hwang AY, Smith SM, Gums JG. Adrenal gland disorders. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 10th ed.New York, NY: McGraw-Hill; 2017. http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861&sectionid=134128262. Accessed May 16, 2019.
  39. Ragnarrson O, Johannson G. Cushing’s syndrome: a structured short-and long-term management plan for patients in remission. Eur J Endocrinol. 2013;169(5):139-152.
  40. Ciato D, Mumbach AG, Paez-Pereda M, Stalla GK. Currently used and investigational drugs for Cushing’s disease. Expert Opin Investig Drugs. 2017;26(1):75-84.
  41. Tritos NA, Biller BMK. Medical therapy for Cushing’s syndrome in the twenty-first century. Endocrinol Metab Clin North Am. 2018;47(2):427-440.
  42. Rubinstein G, Osswald A, Zopp S, et al. Therapeutic options after surgical failure in Cushing’s disease: a critical review [published online ahead of print, April 16, 2019]. Best Pract Res Clin Endocrinol Metab. doi: 10.1016/j.beem.2019.04.004.
  43. Morgan FH, Laufgraben MJ. Mifepristone for management of Cushing’s syndrome. Pharmacotherapy. 2013;33(3):319-329.
  44. UpToDate [database online]. Waltham, MA: Wolters Kluwer; 2019. www.uptodate.com. Accessed May 16, 2019.
  45. Nieman LK, Biller BM, Findling JW, et al. Treatment of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(8):2807-2831.
  46. Funder JW, Carey RM, Mantero F, et al. The management of primary aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(5):1889-1916.
  47. Husebye ES, Allolio B, Arlt W, et al. Consensus statement on the diagnosis, treatment, and follow-up of patients with primary adrenal insufficiency. J Intern Med. 2014;275(2):104-115.
  48. Øksnes M, Ross R, Løvås K. Optimal glucocorticoid replacement in adrenal insufficiency. Best Pract Res Clin Endocrinol Metab. 2015;29(1):3-15.
  49. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(2):364-389.
  50. Ellis AW, Davis C, Brown M, et al. Diabetes. In: Ellis AW, Sherman JJ, eds. Community and Clinical Pharmacy Services: A Step-by-Step Approach. New York, NY: McGraw-Hill; 2013. http://accesspharmacy.mhmedical.com/content.aspx?bookid=684&Sectionid=45145846. Accessed May 17, 2019.
  51. Medication therapy management in pharmacy practice: core elements of an MTM service model: version 2.0. American Pharmacists Association. https://portal.pharmacist.com/mtm_library. Updated March 2008. Accessed May 17, 2019.

Back to Top