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Diabetic Medications

2.50 Contact Hours
This course is applicable for the following professions:
Advanced Registered Nurse Practitioner (ARNP), Certified Registered Nurse Anesthetist (CRNA), Clinical Nurse Specialist (CNS), Licensed Practical Nurse (LPN), Licensed Vocational Nurses (LVN), Midwife (MW), Nursing Student, Registered Nurse (RN)
This course will be updated or discontinued on or before Sunday, April 11, 2021
Course Description
This course covers medications used to treat types 1 and 2 diabetes. Learners will be provided with information on how to safely administer anti-hyperglycemic meds to maintain glycemic control.
CEUFast Inc. did not endorse any product, or receive any commercial support or sponsorship for this course. The Planning Committee and Authors do not have any conflict of interest.

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To earn of certificate of completion you have one of two options:
  1. Take test and pass with a score of at least 80%
  2. Reflect on practice impact by completing self-reflection, self-assessment and course evaluation.
    (NOTE: Some approval agencies and organizations require you to take a test and self reflection is NOT an option.)
Author:    Dana Bartlett (RN, BSN, MA, MA, CSPI)

Outcomes

Participants will discuss the oral and injectable medications that are used to treat types 1 and 2 diabetes mellitus.

Objectives

After completing this continuing education course, the participant will be able to meet the following objectives:

  1. Identify the basic mechanisms of action of the anti-hyperglycemics.
  2. Identify the basic mechanisms of action of injectable medications used to treat type 1 diabetes.
  3. Discuss adverse effects specific to each type of diabetic medication.
  4. Discuss assessments that should be done prior to and during therapy with diabetic medications.
  5. Discuss the issues regarding glycemic control in patients who have type 2 diabetes.

Introduction

Diabetes mellitus is a huge public health problem. Approximately 30.3 million (9.4%) Americans have diabetes mellitus, 7.2 million have the disease but are undiagnosed, and 84.1 million (33.9%) US adults have pre-diabetes.1 In addition, the prevalence of diabetes mellitus has been steadily increasing since the late 1950s2 and despite improvements in the number of people who have attained the recommended A1C level,3 there are still many, many Americans who have not achieved glycemic control.3

In the coming years, nurses will be caring for more patients with diabetes than ever before, and they will need a comprehensive understanding of the medications used for maintaining glycemic control. This module will provide professional nurses with the information they need to administer anti-hyperglycemic medications safely.

The term diabetes mellitus is used to distinguish this disease from diabetes insipidus. For the remainder of the module, the term diabetes will be used to identify diabetes mellitus.

The primary derangement of type 1 and type 2 diabetes is hyperglycemia, elevated blood glucose caused by the absence of insulin production (type 1 diabetes) or decreased insulin production and increased insulin resistance (type 2 diabetes). Chronic hyperglycemia is the defining characteristic of the disease, it is the primary cause of the microvascular complications of diabetes, i.e., retinopathy, nephropathy, and neuropathy,4-6 and it is a contributing factor in the pathogenesis of cardiovascular disease in patients who have diabetes.

There is a direct relationship of the level and duration of hyperglycemia and the incidence of microvascular and macrovascular complications, and in addition, the level and duration of hyperglycemia have a negative effect on the progression of diabetes.

Patients who have type 1 diabetes must use insulin and for patients who have type 2 diabetes, initiation of pharmacologic therapy with an oral hypoglycemic at the time of diagnosis is usually recommended.7 There is strong evidence that remission of type 2 diabetes by way of lifestyle changes like weight loss, exercise, and (possibly) smoking cessation can be attained.8,9 These interventions can help with glycemic control 9,10, 12-15 and they have value for diabetic patients aside from their role in glycemic control. However, for the reasons listed below, glycemic control in type 2 diabetes will, in effect, require the use of medications, often multiple medications, and many patients who have type 2 diabetes will eventually need insulin.16-18

  • Beta-cell dysfunction is often significantly decreased by the time of diagnosis.10
  • Remission of type 2 diabetes requires long-term changes in lifestyle like a significant level of weight loss8,9 and many people, diabetic or not, cannot lose weight and/or adhere to an exercise program or stop smoking.
  • The natural history of type 2 diabetes involves progressive beta cell dysfunction and increased insulin resistance over time.11,16,17,19
  • Early pharmacologic treatment that is started before HbA1c is significantly elevated can improve long-term glycemic control and decrease the risk of long-term complications.7

Given the number of people who have diabetes, the widespread use of anti-hyperglycemics, and the complex pharmacological regimens used to treat the disease, it is imperative that nurses understand the mechanisms by which the anti-hyperglycemics control HbA1c and blood glucose, the risks and benefits of the anti-hyperglycemics, and how and for whom these drugs should be used.

The first section of the module will discuss the mechanism (s) of action, the dosages, indicated use, adverse effects, and contraindications of each of the anti-hyperglycemic medications. The information in this section was obtained from package inserts and from Lexicomp®, a widely used and frequently updated drug database. Pharmacokinetic information for each drug was supplied when it was available. The adverse effects discussed here are the ones that are mentioned most prominently in Lexicomp®, in the package inserts, and the medical literature. Combination products of the oral anti-hyperglycemics are available, but these will not be discussed. Generic names are used first, and brand names are in parentheses. The second section of the module will provide detailed information on the risks and benefits of each drug and outline how, when and for whom they are used.

Injectable Diabetic Medications

Insulin

Mechanism of Action

Insulin binds with insulin receptors on cell membranes. Insulin-insulin receptor binding moves the GLUT4 and GLUT2 insulin transporter molecules to the cell membranes, allowing diffusion of glucose into the cells.

Indications for Use

Insulin is used for the treatment of type 1 and type 2 diabetes.

Pharmacokinetics

The insulins are classified by their onset of action:

  1. Rapid-acting
  2. Short-acting
  3. Intermediate-acting
  4. Intermediate to long-acting
  5. Long-acting

There are also combination products. Regular and NPH are human insulins; the others listed are insulin analogs; the difference between the two will be explained later. Insulins are typically 100 units per mL, aka U-100, but U-500 concentrations are available.

Available Preparations

Insulins are rapid-acting, short-acting, intermediate-acting, long-acting, and combination preparations. Brand names are in parentheses; not all the brand names are listed.

Many of the insulins in use today are analogues. Analogue insulin is insulin that has been genetically engineered to change its absorption, distribution, metabolism, and excretion, and these changes can provide advantages in of glycemic control.

Biochemical and physical barriers and manufacturing challenges have, to this point, prevented the development of an oral insulin preparation.

Rapid-Acting
  1. Insulin lispro (Humalog®): Onset of action, 0.25-0.5 h; peak glycemic effect, 0.5-2.5 h; duration, ≤ 5 h.
  2. Insulin aspart (Novolog®): Onset of action, 0.2-0.3 h; peak glycemic effect, 1-3 h; duration of action, 3-5 h.
  3. Insulin glulisine (Apidra®): Onset of action, 0.2-0.5 h; peak glycemic effect, 1.6-2.8 h; duration, 3-4 h.
Short-Acting
  1. Insulin, regular U-100 (Humulin® R, Novolin® R): Onset of action, 0.25-0.5 h; peak glycemic effect, 2.5-5 h; duration, 4-12 h.
  2. Insulin, regular U-500 (Humulin®): Onset of action, 0.25-0,5 h; peak effect, 4-8 h, duration of action 13-24 h.
Intermediate-Acting
  1. Insulin NPH (Humulin® N, Novolin® N): Onset of action, 1-2 h; peak glycemic effect, 4-12 h; duration, 14-24 h.
Intermediate- to Long-Acting
  1. Insulin detemir (Levemir®): Onset of action, 3-4 h; peak glycemic effect, 3-9 h; duration, 6-23 h, dose-dependent. The higher the dose, the longer the duration.
Long-Acting
  1. Insulin degludec (Tresiba®): Onset of action, 1 h; peak effect, 12 h; duration, >24 h
  2. Insulin glargine (Lantus®): Onset of action, 3-6 h; there is no peak glycemic effect; Duration of action, ~ 11 to > 24 h but the duration can be longer.
Combination Products
  1. Insulin aspart protamine suspension (Novolog® Mix 70/30): Onset of action, 10-20 minutes, peak glycemic effect, 1-4 h; duration of action, 18-24 h.
  2. Insulin aspart (Novolog®): Onset of action, 0.3-0.3 h, peak effect, 1-3 h. duration of action, 3-5 h. (Note: Aspart is used in combination with a longer-acting insulin).
  3. Insulin lispro protamine and insulin lispro (Humalog® Mix 75/25, Humalog® Mix 50/50): Insulin lispro is a rapid-acting insulin, and lispro protamine is an intermediate-acting insulin. Onset of action, 0.25-0.5 h; peak glycemic effect of 50/50 is 0.8-4.8 h, peak glycemic effect of 75/25 is 1-6.5 h, duration of action for both is 14-24 h.
  4. Insulin NPH suspension and regular insulin (Humulin® 70/30, Novolin® 70/30): Onset of action, 0.5 h; Peak glycemic effect, 2-12 h; Duration, 18-24 h.

Dosage

Insulin dosages are prescribed to meet the goals of therapy, e.g., the pre-prandial glucose level, the fasting glucose level, and the HbA1c level that are specific for each patient.

Contraindications

  • Hypersensitivity to the drug or to any component of the product
  • Hypoglycemia.

Adverse Reactions

  • Lipoatrophy at the injection site
  • Hypoglycemia

Amylinomimetic

Available Forms

  • Pramlintide (Symlin® Pen).

Mechanism of Action

Pramlintide is a synthetic analog of the hormone amylin. Amylin is secreted by pancreatic β cells along with insulin at a ratio of 1:100. Pramlintide lowers post-prandial glucose by:

  1. Prolonging and slowing gastric emptying
  2. Decreasing post-prandial glucagon secretion
  3. Acting as a centrally-mediated appetite suppressant.

Indications for Use

Pramlintide is used as an adjunctive treatment for patients who have type 1 or type 2 diabetes who have not attained optimal glycemic control using insulin.

Pharmacokenitics

  • Time to peak plasma is 20 minutes.
  • The duration of action is approximately 3 hours.

Dosage

  1. Type 1 diabetes:
    1. 15 mcg given subcutaneously immediately before a major meal.
    2. The dose can be titrated in increments of 15 mcg every 3 days (If the patient doesn’t have significant nausea) to a dose of 30-60 mcg.
  2. Type 2 diabetes:
    1. 60 mcg given subcutaneously immediately before a major meal.
    2. After 3 days, increase the dose to 120 mcg before each major meal if no significant nausea occurs (If nausea occurs at the 120-mcg dose, reduce the dose to 60 mcg).

When pramlintide is being started, reduce the pre-prandial insulin dose by 50%.

Contraindications

  • Hypersensitivity to the product or to any component of the product.
  • Gastroparesis
  • Hypoglycemia unawareness
  • Severe hypoglycemia

Adverse Effects

  • Occurs in >10%
    • Anorexia
    • Headache
    • Nausea and vomiting
    • In patients who have type 1 diabetes, severe hypoglycemia can occur.

GLP-1 Receptor Agonists

Available Forms

  • Dulaglutide (Trulicity®)
  • Exenatide (Byetta®)
  • Liraglutide (Victoza®)
  • Lixisenatide (Adlyxin®)
  • Semaglutide (Ozempic®)

Mechanism of Action

The GLP-1 receptor agonists are analogs of human glucagon-like peptide-1 (GLP-1), an incretin hormone. The incretin hormones decrease blood glucose by increasing the secretion and release of insulin in response to food and decreasing glucagon secretion. Dulaglutide, exenatide, liraglutide, lixisenatide, and semaglutide are GLP-1 receptor agonists. They bind to and activate GLP-1 receptors on the pancreatic β cells, and as with human incretin, this increases insulin secretion and release. The GLP-1 receptor agonists also slow gastric emptying, regulate post-prandial glucagon secretion, and enhance satiety.

Indications for Use

As an adjunctive treatment, along with diet and exercise, for attaining hyperglycemic control in patients who have type 2 diabetes. Liraglutide is also indicated for reducing the risk of major cardiovascular events in patients who have type 2 diabetes and cardiovascular disease.

Pharmacotinetics

Exenatide, time to peak plasma level, immediate release formulation, 2.1 h. In most people, exenatide concentrations are measurable for ~ 10-hours post-injection.

  • Liraglutide, time to peak plasma level, 8-12 h
  • Dulaglutide, time to peak plasma is 24-72 h
  • Semaglutide, time to peak plasma is 1-3 days
  • Lixisenatide, time to peak plasma is 1-3.5 h

Dosage

These drugs are injected subcutaneously (SC).

  1. Dulaglutide:
    1. The starting dosage is 0.75 mg once a week.
    2. The dosage may be increased to 1.5 mg a week if needed.
  2. Exenatide:
    1. The immediate release formulation is given twice daily, 5 mcg, 60 minutes before a meal.
    2. The dosage can be increased to 10 mcg twice a day after 1 month if 5 mcg is not effective.
    3. The extended-release formulation dose is 2 mg given once a week, with or without meals.
  3. Liraglutide:
    1. 0.6 mg, subcutaneously, once a day for one week.
    2. After one week, increase the dosage to 1.2 mg a day.
    3. The dosage can be increased to 1.8 mg a day if needed.
  4. Lixisenatide:
    1. Begin with 10 mcg once a day for 14 days.
    2. After that, increase the dose to 15-20 mcg a day.
  5. Semaglutide:
    1. Begin with 0.25 mg once a week for four weeks.
    2. Increase to 0.5 mg once a week for four weeks and at that point, increase to 1 mg if glycemic control has not been attained.

Contraindications

  • Hypersensitivity to the drug or to any component of the product.
  • Personal or family history of medullary thyroid cancer.
  • Use in patients with multiple endocrine neoplasia syndrome type 2 (MEN2). With exenatide, the contraindication of use in patients who have MENs applies only to the extended release form.
  • These drugs should be used with caution in patients who have chronic kidney disease and a diminished eGFR (Note: This will be discussed in greater detail later in the module).

Adverse Effects

  • Occurs in >10%
    • Dulaglutide:
      • Diarrhea
      • Nausea
      • Vomiting
    • Exenatide:
      • Diarrhea
      • Nausea
      • Injection site reaction
    • Liraglutide:
      • Increased heart rate, 10-20 bpm
      • Headache
      • Constipation
      • Diarrhea
      • Nausea
      • Vomiting
      • Hypoglycemia, 44% when used with a sulfonylurea, 16% when used a monotherapy
    • Lixisenatide:
      • Antibody formation with a decreased hypoglycemic response
      • Gastrointestinal symptoms like nausea
    • Semaglutide:
      • Increased amylase
      • Increased lipase
      • Nausea

Inhaled Insulin

Afrezza

  • Regular insulin
  • Rapid-acting.

Mechanism of Action

Insulin binds with insulin receptors on cell membranes. Insulin-insulin receptor binding moves the GLUT4 and GLUT 2 insulin transporter molecules to the cell membranes, allowing diffusion of glucose into the cells.

Indications for Use

Hyperglycemic control for patients who have type 1 or type 2 diabetes. The efficacy of inhaled insulin and injected insulin appear to be similar, but a lack of patient acceptance and patient discontinuation of its use have limited the popularity of inhaled insulins.

Pharmacokinetics

The onset is 12 minutes, the peak effect is ~ 33-53 minutes, and the duration of action is ~ 190-270 minutes, proportional to the dose.

Dosage

  • If the patient does not take injectable insulin the dosage of Afrezza is 4 units at each meal.
  • If the patient uses injectable insulin the dosage of Afrezza is adjusted according to the insulin dose, e.g., if 9-12 units of insulin are injected per meal, then 12 units of Afrezza should be used.
  • Afrezza is supplied in single-use cartridges of 4, 8, or 12 units that are inserted into a hand-held inhaler.

Contraindications

  • Hypersensitivity to regular insulin or to any component of the product, chronic lung diseases such as asthma or COPD.
  • The possibility of cross-sensitivity of inhaled insulin with injected insulin has not been ruled out.

Adverse Effects

  • >10%
    • Cough
    • Hypoglycemia (67%)

Oral Diabetic Medications

The oral anti-hyperglycemics are discussed based on their mechanisms of action.

a-Glucosidase Inhibitors

Available Forms

  • Acarbose (Precose®)
  • Miglitol (Glyset®)

Mechanism of Action

The α-glucosidase inhibitors lower blood glucose by inhibiting the action of α-glucosidase, an enzyme in the gut that breaks down ingested carbohydrates and disaccharides into glucose. Glucose absorption is delayed, post-prandial glucose is lowered, and the metabolism of sucrose to glucose and fructose is inhibited.

Indications for Use

An adjunctive treatment, along with diet and exercise, to attain glycemic control in patients who have type 2 diabetes.

The α-glucosidase inhibitors are not mentioned in the American Diabetes Association’s (ADA) 2019 Standards of Care or in recent (2019) authoritative reviews as a first-, second- or, third-line treatment for type 2 diabetes20,21 and the adverse effects of diarrhea and flatulence can limit patient acceptance.19,20 The efficacy of acarbose and miglitol appear to be similar.21

Pharmacokinetics

  • The time to peak plasma of the active drug (acarbose) is ~ 1 hour
  • For miglitol, the time to peak plasma is ~ 2-3 hours.

Dosage

  1. Acarbose:
    1. The starting dosage 25 mg, three times a day, taken at the beginning of each meal.
    2. The maintenance dosage should be increased at 4-8-week intervals and should be adjusted based on the 1-hour post-prandial blood glucose, the HbA1c, and patient tolerance.
    3. The maximum daily dose for patients ≤ 60 kg is 50 mg 3 times a day; for patients > 60 kg, the maximum daily dosage is 100 mg three times a day.
  2. Miglitol:
    1. The starting dosage is 25 mg, three times a day, taken at the beginning of each meal.
    2. After 4-8 weeks the dosage can be increased to 50 mg three times.
    3. After ~ 3 months the maximum dosage of 100 mg three times a day can be used.

Contraindications

  • Hypersensitivity to the drug or to any component of the product.
  • The α-glucosidase inhibitors are contraindicated if the patient has cirrhosis, diabetic ketoacidosis, or any of the following gastrointestinal pathologies:
    • Colonic ulceration
    • Cirrhosis
    • Inflammatory bowel disease
    • Intestinal obstruction or a pre-disposition to intestinal obstruction
    • Chronic intestinal diseases that interfere with absorption or digestion
    • Conditions that may deteriorate as a result of increased gas formation in the intestinal tract
  • The area under the curve (AUC) of acarbose is markedly increased if the eGFR is < 30 and for miglitol, there have been no studies in patients who have an eGFR < 25; in both situations the use of the drug is contraindicated.

Adverse Effects

  • >10%
    • Abdominal pain
    • Diarrhea and flatulence: these effects tend to diminish with time

Biguanides

Available Forms

Metformin is the only available biguanide.

Mechanism of Action

  • Metformin decreases hepatic glucose production
  • It decreases the intestinal absorption of glucose
  • It improves insulin sensitivity, thus increasing glucose uptake and utilization

Indications for Use

Hyperglycemic control for patients who have type 2 diabetes when diet and exercise are not enough to attain glycemic control.

Pharmacokinetics

  • The time to peak plasma level is 2-3 hours for the immediate release formulation
  • 7 hours for the extended-release formulation
  • The onset of effects is within several days
  • The maximum effects are seen within two weeks.

Dosage

  • The starting dose for the immediate release preparation is 500 mg 1-2 times a day or 850 mg once a day.
  • The dose can be increased in increments of 500-850 mg at 7-day intervals to a maximum daily dose of 2.25 g a day.
  • The extended-release preparation should be started at 500 mg - 1 g a day.
  • The dose can be increased in increments of 500 mg at 7-day intervals to a maximum daily dose of 2 g. If glycemic control is not attained, the 2 g daily maximum can be given in two doses.

Contraindications

  • Hypersensitivity to the drug or to any component of the product.
  • Renal disease with an eGFR < 30 mL/minute/1.73m2. Note: The use of metformin for patients who have renal disease will be covered later in the module).
  • Acute or chronic metabolic acidosis, with or without coma, including diabetic ketoacidosis.
  • Active or progressive liver disease.
  • Active abuse of alcohol.
  • A comorbidity like unstable CHF or an acute condition like sepsis that may cause hypoxemia or hypoperfusion.
  • The patient has tried metformin before and developed lactic acidosis.
  • Long-term use has been associated with vitamin B12 deficiency.
  • The use of metformin may need to be temporarily discontinued in patients who will be receiving IV iodinated contrast dye as contrast dye can damage renal function which, in turn, could cause an increased metformin level and lactic acidosis. For more information on this topic, check prescribing guidelines or the American College of Radiology ACR Manual of Contrast Media, Version 10.3., 2018.22 The ACR manual is available online and can be accessed using this link.

Adverse Effects

  • >10%
    • Diarrhea, flatulence, nausea, and vomiting
    • Lactic acidosis is a rare but very serious adverse reaction

Bile Acid Sequestrants

Available Forms

  • Colesevelam (Lodalis®)

Mechanism of Action

The mechanism by which colesevelam lowers blood glucose has not been identified. A review of clinical studies found that when colesevelam was used as an adjunctive treatment for type 2 diabetes the average decrease in HbA1c was ~ 0.5%.23 Because of cost, limited effectiveness, and side effects, colesevelam is not often used to treat type 2 diabetes.20

Indications for Use

Glycemic control for patients who have type 2 diabetes, as an adjunct to diet and exercise.

Dosage

  • 3.75 g once a day or 1.875 g twice a day. (Note: This dosing is for the use of colesevelam as a treatment for hyperlipidemia).

Contraindications

  • Hypersensitivity to colesevelam or to any component of the product
  • History of bowel obstruction
  • Triglyceride level > 500 mg/dL
  • Hypertriglyceridemia-induced pancreatitis

Adverse Effects

  • >10%
    • Constipation

Dipeptidyl Peptidase IV (DPP-IV) Inhibitors

Available Forms

  • Alogliptin (Nesina®)
  • Linagliptin (Tradjenta®)
  • Saxigliptin (Onglyza®)
  • Sitagliptin (Januvia®)

Mechanism of Action

Dipeptidyl peptidase IV is an enzyme that is involved in the breakdown of the endogenous incretin hormones GLP-1 and GIP. The incretin hormones decrease glucagon secretion and increase insulin synthesis and release. Inhibition of DPP-IV thus increases the activity of GLP-1 and GIP and lowers blood glucose by increasing insulin secretion and release and by decreasing glucagon secretion.

Indications for Use

Glycemic control for patients who have type 2 diabetes. The DPP-IV inhibitors can be used as monotherapy along with diet and exercise or in combination with other medications.

Pharmacokinetics

The DPP-IV inhibitors are rapidly absorbed, and the peak effect occurs within several hours.

Dosage

  1. Alogliptin:
    1. 25 mg a day.
    2. The dose should be decreased if the patient has renal impairment, i.e., creatinine clearance (CrCL) < 60 mL/minute.
  2. Linagliptin:
    1. 5 mg a day.
  3. Saxagliptin:
    1. 2.5-5 mg a day.
    2. The dose may need to be reduced if saxagliptin is used with insulin or an insulin secretagogue like a sulfonylurea.
  4. Sitagliptin:
    1. 100 mg a day.
    2. If the patient’s eGFR is <45 mL/minute/1.73 m2 the dose should be decreased.

Contraindications

  • Hypersensitivity to the drug or to any component of the product
  • Diabetic ketoacidosis

Dopamine Receptor Agonists

Available Forms

  • Bromocriptine (Cycloset®)

Mechanism of Action

The mechanism of action of bromocriptine that lowers blood glucose has not been identified.20,23

Indications for Use

As an adjunct, along with diet and exercise, to attain glycemic control for patients who have type 2 diabetes. Cycloset is the only form of bromocriptine approved for the treatment of diabetes. Wexler (January 2019) and Lamos et al. write that bromocriptine has only a modest ability to lower glucose and it has frequent gastrointestinal side effects.20,23

Dosage

  • The initial dosage is 0.8 mg once a day.
  • This can be increased in increments of 0.8 mg, weekly.
  • The maximum daily dose is 4.8 mg, taken with food.

Contraindications

  • Hypersensitivity to bromocriptine or to any component of the product
  • Hypersensitivity to ergot alkaloids
  • Pregnancy
  • Syncopal migraine

Adverse Effects

  • >10%
    • Constipation
    • Dizziness
    • Fatigue
    • Headache
    • Nausea
    • Rhinitis
    • Weakness

Meglitinide Analogs

Available Forms

  • Nateglinide (Starlix®)
  • Repaglinide (Prandin®)

Mechanism of Action

The meglitinide analogs increase calcium movement through calcium ion channels in the pancreatic β cells, and the increased intracellular calcium stimulates the release of insulin.

Indications of Use

As an adjunct, along with diet and exercise, to attain glycemic control for patients who have type 2 diabetes.

Pharmacokinetics

  • The onset of action for nateglinide is ~ 20 minutes, the peak effect is 1 hour, and the duration of effect is 4 hours.
  • The onset of action of repaglinide is ~ 15-60 minutes, and the duration of action is 4-6 hours.

Dosage

  1. Nateglinide:
    1. The initial dosage and the maintenance dose are the same: 120 mg, 3 times a day, 1-30 minutes before a meal.
    2. Patients who are close to their HbA1c goal should be started at 60 mg 3 times a day.
  2. Repaglinide:
    1. Patients whose HbA1c is <8%: 0.5 mg before each meal, 2-4 times a day.
    2. Patients whose HbA1c is ≥8%: 1 or 2 mg before each meal, 2-4 times a day.

Dosing adjustments are determined by the blood glucose response, usually fasting blood glucose. Double the pre-prandial dose up to 4 mg until a satisfactory blood glucose response is achieved. There should be at least 1 week between dosage adjustments.

Dosage range: 0.5-4 mg, with meals. The maximum recommended a daily dose of 16 mg.

Contraindications

  • Hypersensitivity to the drug or to any component of the product.
  • Repaglinide: Concurrent treatment with gemfibrozil. Use of the two drugs together can increase the serum level of repaglinide.

Adverse Effects

  • >10%
    • Nateglinide:
      • Upper respiratory infection
    • Repaglinide:
      • Headache
      • Hypoglycemia
      • URI

Sodium-Glucose Co-Transporter Type 2 Inhibitors (SGLT2 Inhibitors)

Available Forms

  • Canagliflozin (Invokana®)
  • Dapagliflozin (Fraxiga®)
  • Empagliflozin (Jardiance®)
  • Ertugliflozin (Steglatro®)

Mechanism of Action

Sodium-glucose co-transporter type 2 (SGLT2) is a glucose transporter that is found in the renal tubules. SGLT2 reabsorbs a significant amount of filtered glucose from the proximal tubules, and inhibition of SGLT2 increases the renal excretion of glucose and lowers plasma glucose.

Indications for Use

  • As an adjunct, along with diet and exercise, to attain glycemic control for patients who have type 2 diabetes.
  • The SGLT2 inhibitors are also prescribed to patients who have type 2 diabetes and are taking metformin to reduce the risk of major cardiovascular events.

Pharmacokinetics

The onset of action of canagliflozin is within 24 hours, and the duration of action is ~ 24 hours.

Dosage

  1. Canagliflozin:
    1. The starting dosage is 100 mg a day, taken before the first meal.
    2. The maximum daily dosage is 300 mg; this can be used only if the patient has a GFR ≥ 60 mL/minute/1.73 m2.
  2. Dapagliflozin:
    1. The starting dosage is 5 mg a day, taken in the morning; this can be increased to 10 mg a day.
    2. Dapagliflozin is not recommended to be used if the eGFR is consistently between 30 and <60 mL/minute/1.73 m2.
  3. Empagliflozin:
    1. The starting dosage is 10 mg a day; this may be increased to 25 mg a day.
  4. Ertugliflozin:
    1. 5 mg a day.
    2. If the drug is tolerated and glycemic control has not been attained, 15 mg a day may be used.

Contraindications

  • Hypersensitivity to the drug or to any component of the product.
  • Canagliflozin: ESRD, patients on dialysis, severe renal impairment. Depending on the drug the use of an SGLT2 inhibitor is contraindicated if the GFR is < 30 mL/minute/1.73 m2; < 45 mL/minute/1.73 m2, or; < 60 mL/minute/1.73 m2 and the SGLT2 inhibitor should be discontinued when the GFR reaches a specific level.
  • Dapagliflozin: Severe renal impairment (eGFR <30 mL/minute/1.73 m2), ESRD, or patients on dialysis.
  • Empagliflozin: Severe renal impairment (eGFR <30 mL/minute/1.73 m2), ESRD, or patients on dialysis.
  • Ertugliflozin: Severe renal impairment (eGFR <30 mL/minute/1.73 m2), ESRD, or patients on dialysis.

Special Warnings

  • The FDA issued a safety warning stating that Fournier’s gangrene, necrotizing fasciitis of the perineum, has been reported with the use of SGLT2 in inhibitors.

Adverse Effects

  • >10%
    • Canagliflozin:
      • Hyperkalemia
      • Genitourinary fungal infections
      • Renal insufficiency
    • Empagliflozin:
      • Genitourinary fungal infections
    • Ertugliflozin:
      • Genitourinary fungal infections

Sulfonylureas

Available Forms

  • Chlorpropamide
  • Glimepiride
  • Glipizide
  • Glyburide
  • Tolbutamide
  • Tolazamide.

Chlorpropamide, tolbutamide, and tolazamide are first-generation sulfonylureas and are rarely prescribed because the second-generation sulfonylureas are safer, better tolerated, and equally effective at controlling blood glucose as the first-generation drugs.

Mechanism of Action

The sulfonylureas bind to SUR1 receptors on the β cells of the pancreas, and this binding stimulates the release of insulin. The sulfonylureas also decrease glycogenolysis and increase insulin sensitivity.

Indications for Use

As an adjunct, along with diet and exercise, to attain glycemic control in patients who have type 2 diabetes.

Pharmacokinetics

  1. Glimepiride:
    1. Peak effect, 2-3 hours.
    2. Duration, 24 hours.
  2. Glipizide:
    1. Duration, 12-24 hours.
  3. Glyburide:
    1. Onset of action is 15-60 minutes
    2. Duration of action is < 24 hours.

Dosage

  1. Glimepiride:
    1. The initial dosage is 1-2 mg a day, taken in the morning.
    2. The dosage may be increased by 1-2 mg every 1-2 weeks if needed.
    3. The maximum daily dosage is 8 mg.
  2. Glipizide:
    1. The dosage for the immediate release formulation is 5 mg a day, taken in the morning.
    2. This can be increased by 2.5-5 mg a day, no more than every several days.
    3. The maximum once a day dose is 15 mg. The maximum divided daily dose is 40 mg, but doses > 20 mg are no more effective than 40 mg.
    4. The extended-release formulation is started at 5 mg a day, and the maximum daily dosage is 20 mg.
  3. Glyburide:
    1. The initial dosage is 2.5-5 mg a day, taken in the morning.
    2. Lower starting dosages can be used if the patient is sensitive to anti-hyperglycemic drugs.
    3. The dosage can be increased by increments of 2.5 mg every week to a maximum of 20 mg a day.

The micronized tablets (Glynase® PresTabs®) are started at 1.5-3 mg a day and taken in the morning. Lower starting dosages can be used if the patient is sensitive to anti-hyperglycemic drugs. The dosage can be increased by increments of 1.5 mg a day, every week. The maximum daily dosage is 12 mg.

Contraindications

  • Hypersensitivity to the drug or to any component of the product. Cross-sensitivity between the sulfonylureas cannot be ruled out
  • Type 1 diabetes, diabetic ketoacidosis, with/without coma
  • Glyburide should be used cautiously in geriatric patients

Adverse Effects

  • >10%
    • Glimepiride: Hypoglycemia

Thiazolidinediones

Available Forms

  • Pioglitazone (Actos®)
  • Rosaglitazone (Avandia®)

Mechanism of Action

The thiazolidinediones lower blood glucose by a number of complex mechanisms that increase insulin utilization and decrease insulin resistance.

Indications for Use

As an adjunct, along with diet and exercise, to attain glycemic control for patients who have type 2 diabetes.

Pharmacokinetics

  • Pioglitazone:
    • Glucose control may take several weeks
  • Rosiglitazone:
    • Glucose control may take several weeks

Dosage

  1. Pioglitazone:
    1. 15-30 mg a day.
    2. If the target HbA1c is not reached, the dosage can be increased in increments of 15 mg to a maximum daily dosage of 45 mg.
    3. Patients should be observed closely for signs/symptoms of heart failure when the dosage is being increased.
    4. Patients who have CHF should receive a starting dose of no more than 15 mg a day.

The dose of insulin or a sulfonylurea should be decreased if the patient is taking pioglitazone.

  1. Rosiglitazone:
    1. 4 mg a day in a single dose or in divided doses, twice a day.
    2. The dosage can be increased in 8-12 weeks if needed to a maximum of 8 mg.
    3. The dose of insulin or a sulfonylurea should be decreased if the patient is taking rosiglitazone.

Contraindications

  • Hypersensitivity to the drug or to any component of the product.
  • The thiazolidinediones can cause or exacerbate CHF, and they should not be used for patients who have symptomatic CHF or patients who have New York Heart Association (NYHA) Class III or IV heart failure.

Adverse Effects

  • >10%
    • Pioglitazone:
      • Edema
      • Hypoglycemia
      • URI
    • Rosiglitazone:
      • Increased HDL and LDL cholesterol
      • Hypoglycemia (when used with insulin)
      • URI
      • Weight gain

Type 1 Diabetes and Diabetic Medications

Patients who have type 1 should start insulin therapy at the time of diagnosis, and insulin therapy will need to be continued for the life of the patient. Research has shown that as many as 74% of people who have had type 1 diabetes for five years or longer still secrete tiny amounts of insulin,24 and some patients who have type 1 diabetes secrete an amount of insulin that is clinically important,24 but insulin therapy is still necessary for type 1 diabetics to survive.

Insulin and Insulin Therapy

The insulin therapy that is currently recommended is often called intensive insulin therapy, and it is intended to mimic as closely as possible the normal physiological profile of insulin secretion and release. This approach has been shown to produce better glycemic control and to significantly reduce the risk of developing diabetic nephropathy, neuropathy, and retinopathy and the cardiovascular complications of diabetes.25-27 The basic goals/objectives and methods of intensive insulin therapy are:25-28

  • An HbA1c of < 7%
  • Glucose level of 70-180 mg/dL
  • Twice a day injection of an intermediate- or long-acting insulin to provide a basal level of insulin or an infusion pump delivering a continuous basal level of rapid-acting insulin
  • Prandial insulin before each meal with a rapid-acting or short-acting insulin
  • The use of insulin analogues is recommended

Glycemic Goals

Glycemic control is the goal of treatment for diabetes, but not all patients can reach the standard HbA1c goal and a lower or higher HbA1c may be acceptable, depending on the patient’s age, co-morbidities, the duration of their disease, and other factors.28

Recombinant Human Insulin Versus Insulin Analogs

Animal-derived insulins are no longer used in the United States, and synthetic insulins, either recombinant human insulin or insulin analogues, are used exclusively, and the insulin analogues are the preparation of choice.25 The insulin analogues are preferred because:

  1. The purpose of insulin therapy is to attain glycemic control without hypoglycemia and to mimic as closely as possible the endogenous basal and post-prandial insulin secretion.29,30
  2. The insulin analogues are better at replicating endogenous insulin secretion patterns than recombinant human insulin.29-31
  3. Insulin analogues have been genetically engineered to change absorption, distribution, metabolism, and excretion, and these changes can provide advantages in attaining glycemic control.
  4. Two examples of the advantages of the pharmacokinetic profiles of the insulin analogues:
    1. Lispro insulin has a quicker onset of action, and a longer duration of action than regular insulin and these effects make it more useful than regular insulin for post-prandial glucose control.30
    2. The long-acting insulin analogues, in contrast, have a slower rate of absorption and a longer duration of action and these pharmacokinetic properties have been shown to reduce the incidence of nocturnal hypoglycemia.29

Insulin Pumps or Injectable Insulin

Continuous subcutaneous insulin infusion (CSII) uses an insulin pump to deliver a continuous basal insulin level of rapid-acting insulin, usually an insulin analogue, and CSII can be used with self-injections of pre-prandial insulin.32 Continuous subcutaneous insulin infusion can be more effective than multiple insulin injections for attaining the optimal HbA1c and preventing hypoglycemia,25,33 but the level of glycemic control depends in part on the type of device that is used; the level of effectiveness can be modest25,33 but with pumps that have continuous glucose monitoring the level of glycemic control can be significant.34

There are no consensus guidelines for choosing between CSII and multiple daily injections and the decision as to which to use depends on cost, patient preference, and which of the two works best for the patient in terms of maintaining the optimal HbA1c level and avoiding hypoglycemia.32

Insulin Pens or Syringes and Vials

Insulin pens are preferred by most patients and compared to syringe and vials, insulin pens are more convenient, the delivered dose is more accurate, glycemic control is better (the dose is consistently more accurate, and the shorter needle length avoids intra-muscular injection), patient adherence to the medication regimen is improved, and the risk of hypoglycemia is less.35,36 In 2017, the Food and Drug Administration (FDA) approved the first insulin pen that can be combined with a smartphone application. This device, the InPen®, automatically tracks many aspects of insulin therapy and helps patients calculate doses and manage their insulin therapy.

Blood Glucose Monitoring

Measuring HbA1c is the primary method of assessing long-term glycemic control,28 and for most patients checking HbA1c every three months or so is enough.28 However, the HbA1c cannot measure glucose level variability or detect hypoglycemia so checking blood glucose is necessary, and self-monitoring of blood glucose should be done before meals, at bedtime, if there are signs and symptoms of hypoglycemia, before exercising, and in other situations.33 This may require checking blood glucose by fingerstick six to 10 times a day, and the need for such frequent blood glucose checks can be reduced by use of a continuous glucose monitoring device (CGM). Continuous glucose monitoring devices can provide better glycemic control (decreased HbA1c) than self-monitoring, their use can reduce the incidence of hypoglycemic events, and these advantages are especially strong for patients who have frequent episodes of hypoglycemia and/or hypoglycemic unawareness.33,37-39 The use of a CGM, however, does not mean that patients never need to check blood glucose.33

Injection Technique and Insulin Efficacy

The amount of insulin that is absorbed can vary significantly from patient to patient and from dose to dose, and there can be intra-patient variation in absorption, as well. The pharmacokinetics of insulin and thus its actions and effectiveness can be influenced by many factors related to the injection process, and optimal insulin injection technique can improve glycemic control.

  1. Intramuscular injection: Intramuscular injection of insulin causes rapid and irregular absorption.40,41
  2. Needle size: Studies have shown that using needle sizes of 4 mm, 5 mm, 6 mm, or 8 mm did not significantly affect insulin absorption42, and regardless of the patient’s body mass index (BMI), there is no need to use a needle > 8 mm in length.43,44
  3. Size of the dose: Increasing the amount of the dose slows absorption.27,41
  4. Skin temperature and local blood flow: Higher skin temperature and/or increased local blood flow caused by exercise, massage, and high ambient skin temperature can increase the absorption of insulin. 27,41 Smoking decreases peripheral blood flow and can decrease insulin absorption.27,41
  5. Injection site: Insulin can be injected in the abdominal wall, buttocks, upper arms, and upper legs,27 and the speed of insulin absorption differs between these sites: it is fastest in the abdominal wall, the slowest in the buttocks, and legs, and in between those two areas for the upper arms.27 All of these areas can be used, but a planned rotation can help reduce day-to-day changes in blood glucose,27 it can reduce HbA1c and reduce the total daily insulin dose,40 and prevent lipoatrophy, lipohypertrophy, and subcutaneous scarring.41 Lipohypertrophy occurs in approximately 50% of diabetic patients43 and injecting insulin into a lipohypertrophic area can significantly reduce insulin absorption and cause erratic insulin absorption.18,41,43
  6. Injection angle and technique: The angle of injection should be 90°.27 Using or not using a lifted skin fold technique will depend on the length of the needle, and if the needle is at least 4 mm, lifting a fold of skin is not needed.45 When using an insulin pen, the needle should be left in place for 5-10 seconds to ensure the dose is delivered and to avoid insulin leaking from the injection site.27,40,46

Self-injection of insulin is not complicated, but newly diagnosed type 1 diabetics will need to be taught the proper techniques, i.e., needle size, angle of injection, etc., as they apply to the patient. Physicians, nurses, and pharmacists can perform the necessary patient teaching, and Certified Diabetes Educators can be especially effective in this role.

Hypoglycemia

Hypoglycemia is a significant complication of type 1 diabetes. Patients who have type 1 diabetes typically have one-two episodes of hypoglycemia per week,47 and as many as one in five of these episodes are severe, severe defined as the patient requires assistance for administration of carbohydrates and/or glucagon.48

Persistent episodes of hypoglycemia cause very serious consequences:

  • Hypoglycemia increases the risk for morbidities like cardiovascular events and dementia49
  • 6%-10% of patients who have type 1 diabetes die from hypoglycemia47
  • Hypoglycemia itself, by initiating a process called hypoglycemia-associated autonomic failure (explained below), will increase the frequency and severity of hypoglycemic episodes.47,49,50

Hypoglycemia in type 1 diabetics is caused by intensive insulin therapy,47,51 but an absolute or relative excess of insulin is not the only cause of hypoglycemia in this patient population; as previously mentioned, hypoglycemic episodes cause hypoglycemia. Patients who have continued and persistent episodes of hypoglycemia develop an abnormal response to low blood sugar that is characterized by decreased glucagon and epinephrine excretion and decreased suppression of insulin secretion, a phenomenon that is called hypoglycemia-associated autonomic failure.52 This change in the normal compensatory responses to hypoglycemia causes hypoglycemia and decreases awareness of hypoglycemia which, in turn, prevents self-treatment and predisposes the patient to more episodes of hypoglycemia,49 creating a vicious cycle of more frequent and more severe hypoglycemia. The latter phenomenon, which is called hypoglycemia unawareness, and it occurs in approximately 17%-50% of patients who have type 1 diabetes.48,49

Table 1: Definitions of Hypoglycemia49,53

Severe Hypoglycemia

The patient requires the assistance of another person to administer carbohydrate, glucagon, or another resuscitative action.

Neurologic recovery that results from restoring plasma glucose to normal is considered enough evidence that the event was caused by hypoglycemia

Documented Symptomatic

Typical signs and symptoms of hypoglycemia and a documented glucose of ≤70 mg/dL

Asymptomatic

Blood glucose of ≤ 70 mg/dL but no signs or symptoms of hypoglycemia

Probable

Typical hypoglycemia signs and symptoms of hypoglycemia, but blood glucose was not measured

Pseudo-Hypoglycemia

An event during which the diabetic person has the typical symptoms of hypoglycemia with measured plasma glucose > 70 mg/dL

Patient Adherence to and Compliance with Insulin Therapy

Sub-optimal adherence to and compliance with a prescribed insulin regimen is a common problem.54 Farsaei et al. (2014) found that 14.3% of type 1 diabetics had low adherence and 63.4% had medium adherence to their insulin regimens. Non-adherence can be due to factors such as the number of daily injections, embarrassment, feeling worse after an insulin injection, forgetfulness, injection site pain, perceived time-consuming nature of the regimen, and weight gain.54

Pramlintide and Type 1 Diabetes

Pramlintide is the only drug other than insulin that has an FDA-approved use for the treatment of type 1 diabetes. Pramlintide has been shown to decrease HbA1c, lower body weight and reduce postprandial hyperglycemia, and it may help reduce the total daily insulin dose.25,55,56 The need for additional injections would be a disincentive to add pramlintide to an insulin regimen.

Metformin, DPP-IV inhibitor, GLP receptor inhibitors, and SGLT2 inhibitors have been used to treat type 1 diabetes, and there is evidence that they can be beneficial,55,56 but the American Diabetes Association (ADA) does not recommend their use, stating: “The risks and benefits of adjunctive agents beyond pramlintide in type 1 diabetes continue to be evaluated through the regulatory process; however, at this time, these adjunctive agents are not approved in the context of type 1 diabetes."18

Type 2 Diabetes and Diabetic Medications

Starting Therapy

Metformin is the drug of choice for starting treatment in patients who have type 2 diabetes,25 and there are many reasons why it is recommended as the first medication for newly diagnosed type 2 diabetics:25,57,58

  • Considerable clinical experience with its use
  • Metformin is very effective
  • Inexpensive
  • No risk of hypoglycemia when used as monotherapy
  • No weight gain, possible weight loss or at least weight stabilization
  • Adverse effects are typically mild and diminish after several weeks of therapy
  • Possible protective effect against CV events in certain patient populations
  • Adverse effects from metformin that may cause serious harm - lactic acidosis and B12 deficiency causing anemia or neuropathy are rare.

Metformin clearly causes B12 deficiency and significantly lowers serum B12 concentrations.57,59 The risk for these complications increases with dose and duration of metformin use,57,59 but although there have been reports of anemia and peripheral neuropathy caused by metformin a recent (January 2019) meta-analysis concluded that there is no significant (italics added) association between metformin use and developing anemia or neuropathy.59 Nonetheless, the ADA recommends that periodic measurement of B12 should be considered, particularly if the patient develops anemia or peripheral neuropathy.25

Lactic acidosis is a rare complication of metformin use25,57 with an estimated incidence of 5 cases per 100,000 patient-years, but it is clinically quite important because the fatality rate of metformin-induced lactic acidosis can be as high as 45%.60 Metformin is metabolized by the liver, and it is excreted by the kidneys. Typically, patients who develop metformin-induced lactic acidosis have renal impairment, a co-morbidity that decreases renal perfusion and/or causes hypoperfusion and hypoxemia,57 or comorbidity that prevents lactate metabolism or increases the production of lactate.57,61 These co-morbidities include age of 80+ years, alcohol abuse, chronic obstructive pulmonary disease, hepatic dysfunction, heart failure, hypoglycemia, a history of lactic acidosis, or renal insufficiency. These conditions are usually considered to be contraindications to the use of metformin or at least, cautions for its use; for example, the use of metformin is contraindicated in patients who have an eGFR < 30 mL/min, and therapy with metformin should not be started if the eGFR is between 30 and 45 mL/min. The strength and importance of these co-morbidities as risk factors for metformin-induced lactic acidosis is still not clear.61

If the use of metformin is contraindicated or metformin is not tolerated, an oral hypoglycemic should be prescribed, and the drug should be chosen based on these factors:

  • Adverse profile of the medication, e.g., potential for hypoglycemia or weight gain
  • Availability
  • Benefits, e.g., potential for the drug to reduce the risk for CV events or to promote weight loss
  • Contraindications for use
  • Cost
  • Drug-drug interactions
  • Patient preference
  • The patient’s co-morbidities

Metformin is contraindicated if the patient has an eGFR of < 30 mL/minute; active or progressive liver disease; active abuse of alcohol; there is a comorbidity like unstable CHF or an acute condition like sepsis that may cause hypoxemia or hypoperfusion; the patient has tried metformin before and developed lactic acidosis, or; the patient has acute or chronic metabolic acidosis, with or without coma, including diabetic ketoacidosis.57

Adding Another Anti-hyperglycemic

If glycemic control is not attained after three months of treatment with metformin and lifestyle interventions25 another drug should be added to the regimen.7,25

There is little head-to-head research comparing the efficacy and long-term safety of the second-line and third-line line diabetic medications,7 and there is little research about the advantages/disadvantage of any specific combination of oral hypoglycemics.62 Given those limitations, deciding which drug to add to the regimen will depend on the basic principles of drug prescribing that were previously mentioned, e.g., cost, adverse effect profile, risks and benefits, and comorbidities.25

Example: Despite the use of metformin and lifestyle interventions, the HbA1c is not at the desired level. The patient has atherosclerotic cardiovascular disease (ASCVD) and normal renal function, an eGFR of 75 mL/minute. The GLP- 1 receptor agonists and the SGLT2 receptor inhibitors have been shown to reduce the risk for major CV events, and as the renal function is normal, an SGLT2 receptor inhibitor can be used, and either one of these drugs is appropriate for this situation.

If a second medication is required, clinicians can refer to guidelines published by the ADA.25 The guidelines are described in the following paragraphs, but they can be viewed online by linking to the journal site: American Diabetes Association. 9 Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019;42(Suppl 1): S90-S102.

  1. The HbA1c is not at the desired level/no ASCVD or CKD: If metformin and lifestyle intervention do not lower the HbA1c and the patient does not have established ASCVD or chronic kidney disease (CKD) a second drug should be added to the regimen.7,25
    1. In this situation the ADA recommends using a GLP-1 agonist, a thiazolidinedione, an SGLT2 inhibitor, or a DPP-IV inhibitor; no preference for one over another is given.25 If adding one of these does not lower the HbA1c, add the other the regimen, a GLPI-1 doesn‘t work, try an SGLT2 inhibitor or one of the other drugs, and if that is not successful a sulfonylurea or basal insulin would be the next step.25
  2. The HbA1c is not at the desired level/the patient has ASCVD or CKD, or CHF: For patients who have ASCVD, prescribe an SGLT2 inhibitor that that has been shown by a cardiovascular outcome trial to have positive effect for reducing the risk for CV events or a GLP-1 receptor agonist that has a labeled use and a proven benefit for reducing the risk for CV events: liraglutide, semaglutide, or extended release exenatide, or canagliflozin or empagliflozin.25 If this approach is not successful, or the patient cannot tolerate the GLP-1 agonist or the SGLT2 inhibitor, use the drug that was not prescribed, a DPP-IV inhibitor if the patient is not taking a GLP-1 agonist, a sulfonylurea, basal insulin, or a thiazolidinedione.25
    1. For patients who have CKD or CHF, prescribe an SGLT2 inhibitor that has been shown through a cardiovascular outcome trial to reduce CHF and/or CKD if the eGFR is adequate; canagliflozin or empagliflozin.25 If the eGFR is not adequate, prescribe a GLP-1 agonist that that has a labeled use and a proven benefit for reducing risk CV events: liraglutide, semaglutide, or extended release exenatide.25
    2. If these approaches are not successful, do not use a thiazolidinedione if the patient has CHF. Use a GLP-1 agonist or an SGLT2 receptor inhibitor that has been shown through a cardiovascular outcome trial to reduce the risk for CV events: liraglutide, semaglutide, or exenatide, or canagliflozin or empagliflozin.25 Basal insulin or a sulfonylurea can be used, as well.25
  3. The HbA1c is not at the desired level, and it is very important that the patient loses weight: Prescribe an SGLT2 receptor inhibitor or a GLP-1 agonist that has been proven to promote weight loss; in descending order the preference would be semaglutide, liraglutide, dulaglutide, exenatide, or lixisenatide.25
    1. If this approach fails, try the other medication, i.e., if the patient was taking a GLP-1 agonist, use an SGLT2 receptor inhibitor and if that is unsuccessful, metformin, an SGLT2 receptor inhibitor, and a GLP-1 agonist can be used together. If the HbA1c is still not lowered using a DPP-IV inhibitor (if the patient is not taking a GLP-1 agonist) and finally, try basal insulin, a sulfonylurea, or a thiazolidinedione.25

Bromocriptine, α-glucosidase inhibitors, colesevelam, and pramlintide are not mentioned in the ADA Standards of Care - Pharmacologic Approaches to Glycemic Treatment 25 and these drugs are not typically recommended for treatment of type 2 diabetes20 because they have limited efficacy and they have side effects that can be difficult to tolerate.63,64

Insulin as the First Therapy for Type 2 Diabetes

If the patient has signs of catabolism, the HbA1c is > 10%, or the blood glucose is > 300 mg/dL, consider starting therapy with insulin.25 Metformin can be started along with insulin,7 and the patient has ketonuria but no weight loss a GLP-1 agonist or insulin can be used.7 Starting therapy with a sulfonylurea can be done, as well, if insulin therapy will be difficult for the patient.7

Short-term intensive insulin therapy initiated soon after diagnosis of type 2 diabetes has been shown to reverse beta-cell dysfunction, decrease insulin resistance, and preserve beta-cell function, and it can produce long-lasting hypoglycemic control and drug-free remission of the disease.65-69 There are considerable research and clinical experience that supports the effectiveness of this approach, but the difficulty in identifying patients that will benefit and the time and effort involved are barriers to its use,67,68,69 and it has not been widely used.17

Insulin and Type 2 Diabetes

Most patients who have type 2 diabetes will eventually fail to meet the target HbA1c level and attain glycemic control, and because damage to beta-cells is progressive, insulin therapy will eventually be needed.17 Insulin can prevent microvascular complications, and it can help the patient attain glycemic control,70 but as with any diabetic therapy, there are benefits and risks. Insulin therapy increases the risk for hypoglycemia, and because insulin resistance and associated hyperinsulinemia are part of the pathophysiology of type 2 diabetes, exogenous insulin increases insulin levels and may cause weight gain, hypoglycemia, increase the risk of developing metabolic syndrome, and worsen the level of insulin resistance.70

The barriers that prevent early and effective use of insulin and adherence to insulin therapy in patients who have type 2 diabetes are significant but certainly are not insurmountable. Key points for patient education should include:

  • Fear of failure: Many people with diabetes see the use of insulin as representing failure. It is true that a patient’s inability to adhere to lifestyle changes contributes to the progression of diabetes, but patients should be reminded that diabetes, in many cases for reasons that cannot be controlled, is a progressive disease.
  • Diabetics need insulin: All diabetics to some degree have a lack of insulin. Injecting is simply a way of providing the body with what it needs.
  • Insulin has many benefits: Patients who have type 2 diabetes and need insulin should be told that insulin provides benefits that are not available from oral antihyperglycemics. The primary benefit is a more effective way of controlling blood sugar and this, in turn, reduces the risk of diabetic complications and can slow the progression of diabetic complications. Insulin is also more effective than the oral anti-hyperglycemics at lowering HbA1c.
  • Insulin therapy is not always permanent: Some patients may need insulin for only brief periods of time.
  • Fear of pain: The needles used to inject insulin are very fine, and an injection into subcutaneous tissue is relatively less painful than intramuscular injections or other procedures that involve needles. Pain is subjective but it reasonable to say that the pain of an insulin injection is brief and minor.
  • Insulin therapy is not complicated: Insulin therapy can seem to be complex, but with proper teaching, most patients quickly learn that using insulin and monitoring blood sugar are simple. In addition, insulin therapy is one sense frees patients from concerns about future complications and provides more control of the disease.

Hypoglycemia and Type 2 Diabetes

Hypoglycemia is less common in patients who have type 2 diabetes than type 1 diabetes, but it is still a significant concern, particularly if the patient is taking a sulfonylurea and/or insulin or for elderly diabetic patients.71 Bromocriptine, α-glucosidase inhibitors, colesevelam, metformin, amylin agonists, DPP-IV inhibitors, GLP-1 agonists, SGLT2 receptor inhibitors, and the thiazolidinediones do not, by themselves cause hypoglycemia.53,62

Diabetic Medications and Complications

Cardiovascular disease, nephropathy, and weight gain are common in patients who have diabetes, and these issues must be considered when using diabetic medications.

  • Diabetic medications can have a negative effect on the progression of CVD disease, and some have been associated with, or can cause major CV events of CHF.
  • Impaired/diminished renal function, which is common in many diabetic patients, can decrease the excretion of some diabetic medications and this can cause significant complications.
  • Some of the diabetic medications can cause increased body weight, making glycemic control difficult.

Cardiovascular Disease

α-glucosidase inhibitors: Acarbose may reduce the risk of CV events, but the evidence for this effect is limited, conflicting, and inconclusive.72

Biguanides: Metformin can cause lactic acidosis, and because of this, current guidelines recommend that metformin not be used in patients who have unstable CHF, patients who have CHF and are hospitalized, or patients who have CHF and an eGFR of 30 ml/minute.25 Metformin can be used in patients who have stable CHF and an eGFR > 30 mL/minute or a serum creatine < 1.5 mg/dL and for these people, the risk of lactic acidosis is very low.73 There is evidence that for patients who have type 2 diabetes metformin may actually reduce the risk of developing CHF, reduce mortality from CHF, and improve the progression of the disease,74,75 but these conclusions have not been confirmed by large-scale research.74,75

For certain type 2 diabetic patients, e.g., those who are obese, who have established CAD, or who are taking insulin, metformin can decrease the risk for, and incidence of CV events like MI and stroke,57 and it may decrease mortality caused by diabetes, but the evidence for these benefits comes from two randomized, placebo-controlled studies, and several observational cohort studies.76

Colesevelam: Colesevelam can help reduce the risk of developing CAD.77

Dipeptidyl peptidase IV (DPP- IV) inhibitors: The SAVOR-TIMI 53 study clearly showed that for patients who have type 2 diabetes the use of saxagliptin significantly increased the risk for hospitalization because of heart failure,25,78-80 but the prescribing information for the other DPP-IV inhibitors simply states that these drugs should be used cautiously in patients who have heart failure or kidney failure. At this time, no causal mechanism of action linking DPP-IV inhibitors with heart failure has been identified, it is not clear if the risk for heart failure is specific to saxagliptin or it is a class effect shared by all the DPP-IV inhibitors, or the increased risk is likely only in patients who have CVD, heart failure, or kidney disease.78 A recent literature review and the ADA 2019 Standards of Care both concluded that alogliptin, linagliptin, and sitagliptin do not increase the risk for heart failure.80,81 (Note: Alogliptin is no longer manufactured)

The DDP-IV inhibitors have not been shown to have a negative effect on the development of ASCVD.78

GLP-1 receptor agonists: The GLP-1 receptor agonists are recommended by the ADA for patients who have type 2 diabetes and CVD25 and for patients whose HbA1c is not controlled by metformin or who cannot take metformin.25

Liraglutide has an FDA-approved use for reducing the risk of major CV events: death from CV, MI, and stroke.

Research has confirmed that liraglutide can reduce the risk for significant CV effects,80, 82-84 but this protective effect appears to vary between the GLP-receptor agonists.80,82,85 Semaglutide may reduce this risk 80,82,83 but extended release exenatide and lixisenatide do not appear to have this benefit,80,82,83 and although the ADA recommends using GLP-1 receptor agonists for patients who have type 2 diabetes and CVD, the 2019 Standards of Medical Care Pharmacologic - Approaches to Glycemic Treatment states that for this situation a GLP-1 receptor agonist with proven CVD benefit should be used: “Proven CVD benefit means it has a label indication of reducing CV events. For GLP-1RA evidence strongest for liraglutide > semaglutide > exenatide extended release.”25

There is no evidence that the GLP-1 receptor agonists increase the risk of developing heart failure or increase the risk of being hospitalized because of heart failure.80

SGLT2 receptor inhibitors: The SGLT2 receptor inhibitors are recommended by the ADA for patients who have type 2 diabetes and CVD,25 and canagliflozin and empagliflozin both have an FDA-approved use for reducing the risk of major CV events - death from CVD, MI, and stroke - in patients who have type 2 diabetes. Evidence from placebo-controlled trials of canagliflozin and empagliflozin clearly showed that both drugs significantly reduced death from CVD and reduced the incidence of MI and stroke.80,86,87 The ADA also recommends using canagliflozin or empagliflozin for patients whose HbA1c is not controlled by metformin or who cannot take metformin and who have CHF,25 and again, there is strong evidence that these SLGLT2 receptors reduce the risk of hospitalization from CHF80,81,88 and they may prevent the development of CHF, as well.80,88 The ADA 2019 Standards of Care - Pharmacologic Approaches to Glycemic Treatment states: “Both empagliflozin and canagliflozin have shown a reduction in HF in CVOTs (Cardiovascular outcomes trials).”25

Sulfonylureas: The second-generation sulfonylureas used in the United States, glimepiride, glipizide, and glyburide, do not appear to increase the risk for major CV events.89,90 Compared to metformin DPP-IV inhibitors, GLP-1 receptor agonists, and thiazolidinediones their risk for this is higher, but data on sulfonylureas and CV risk has been limited to small studies that were not specifically designed to study the CV safety of the sulfonylureas and direct, controlled trials of this issue have not been done.89,90

There is little information about the sulfonylureas and the risk for heart failure,91,92 and the data that is available cannot be used to determine their safety vis a vis heart failure. It is interesting to note that the ADA recommends that for patients who are taking metformin, who have not attained glycemic control, and who have CHF, the sulfonylureas are considered a second-line choice to be used if an SGLT2 receptor inhibitor or a GLP-1 agonist is not successful.25

Thiazolidinediones: Pioglitazone does not increase the risk of CV events or CVD disease-related death, and it may slow the progression of CVD.93,94 Research on rosiglitazone and an increased risk for CV events has been inconclusive.95 Both pioglitazone and rosiglitazone can increase the risk of developing heart failure, and the prescribing information for both drugs contains a US Boxed Warning stating that pioglitazone and rosiglitazone can cause or exacerbate CHF and that they should not be used for patients who have symptomatic heart failure or who have NYHA class III or IV heart failure.

Table 2: New York Heart Association Functional Classification

Class I

Cardiac disease, but no symptoms and no limitations in ordinary physical activity, e.g., no shortness of breath when walking or climbing stairs

Class II

Mild symptoms (mild shortness of breath or angina) and slight limitation during ordinary activity

Class III

Marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g., walking short distances (20-100 m). Comfortable only at rest

Class IV

Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients

Insulin: Insulin has not been associated with an increased risk for CV events or CHF.66,96

Amylinometic: Pramlintide has not been associated with an increased risk for major CV events.97

Impaired Renal Function

α-glucosidase inhibitors: Acarbose is not recommended if the serum creatinine is >2 mg/dL or the CrCl is <25 ml/minute/1.73 m2 because in patients who have significant renal impairment, the AUC can be increased 6-fold. The primary concern is that acarbose has been reported to cause liver injury (This will be discussed later) and impaired renal function might then further increase the risk of hepatic damage; a recent (2018) review did not support this.98

Miglitol is not recommended if the CrCl is <25 ml/minute/1.73 m2 because the drug is primarily renally excreted and because its use in this clinical situation has not been extensively studied.

Biguanides: The issue of impaired renal function and metformin was previously discussed.

DPP-IV Inhibitors: Alogliptin, saxagliptin, and sitagliptin are primarily excreted by the kidneys, and the dose should be decreased in patients who have impaired renal function. The clinical effects of the use of these drugs in patients with impaired renal function have not been well studied,99,100 and the prescribing information for alogliptin, saxagliptin and sitagliptin advise that they are used with caution in this patient population.

There is no need to adjust the dose of linagliptin in patients who have renal impairment.

The ADA recommends that for patients who are taking metformin, who have not attained glycemic control, and who have CKD, DPP-IV inhibitors are considered a second-line choice to be used if an SGLT2 receptor inhibitor or a GLP-1 agonist is not successful.25

GLP-1 receptor agonists: The prescribing information for the GLP-1 receptor agonists recommends using these drugs with caution if the patient has impaired renal function, particularly when starting therapy or increasing the dose, not using them if the patient has severe renal disease or ESRD, and notes that there are limited experience and limited information about the use of GLP-1 receptor agonists in the context of renal impairment. Seventy-eight cases of acute renal failure or renal insufficiency associated with the use of exenatide have been reported,82 but there is no recent (past 10 years) information about this issue.

Meglitinide analogs: Metabolism of nateglinide produces pharmacologically active metabolites. These metabolites are renally excreted, they can accumulate if the patient has renal impairment, and this may cause hypoglycemia.101

Nateglinide should be used cautiously and at a reduced dose for patients who have severe renal impairment and during initiation of therapy with the drug or when the dose is changed, and patients taking nateglinide should be closely monitored for hypoglycemia, particularly in those situations.

Repaglinide should be used cautiously and at a reduced dose in patients who have decreased renal function; the use of repaglinide in patients who have severe renal impairment (CrCl < 20 mL/minute) or who require hemodialysis has not been studied. During the initiation of therapy with repaglinide or when the dose is changed, the patient should be closely monitored for hypoglycemia.

Sulfonylureas: The sulfonylureas are not known to cause renal damage. Glimepiride and glipizide have a comparatively short duration of action and pharmacologically inactive metabolites, so these drugs are preferred for treating diabetic patients who have CKD;90,100 glyburide is not recommended in patients who have CKD.100 The dose of sulfonylureas should be decreased if the patient has ESRD.

SGLT2 inhibitors: Canagliflozin, empagliflozin, and dapagliflozin can significantly delay the onset and slow the progression of albuminuria, nephropathy, and ESRD, and reduce the risk of death from kidney disease in patients who have type 2 diabetes.102,103 These benefits (Noted during the CANVAS program study) were consistent in patients who had an eGFR of 30–45, 45–60, 60–90, and ≥90 mL/min/1.73 m2, and the ADA recommends that the SGLT2 inhibitors be used for patients who have not attained glycemic control with metformin and who have CKD and an adequate eGFR.25 In addition, several recent (2019) reviews concluded that the risk reduction for renal damage provided by the SGLT inhibitors may benefit patients with, and without CKD.102,103

However, the ADA’s recommendation seems to imply that these drugs should not be used in patients who do not have an adequate eGFR, and the prescribing information for canagliflozin empagliflozin and dapagliflozin advises that the dose should be reduced if the eGFR is below a certain point (different for each drug) or that use is contraindicated is the eGFR is below a certain point.

Based on data from 101 case reports the FDA did issue a warning noting acute renal failure had been observed in patients taking an SGLT inhibitor,104 and this warning is the likely source for the aforementioned cautions and the conflicting information about real impairment/diminished eGFR and the use of these drugs. But research done subsequent to that warning concluded that the SGLT2 inhibitors did not cause acute renal failure,105 and Alicic et al. (2019) wrote that “.. current recommendations to limit use of SGLT2 inhibitors by eGFR criteria may change once results of CREDENCE and other ongoing clinical trials with primary CKD outcomes are reported.”103

Nevertheless, the current prescribing information for the SGLT2 inhibitors recommends:

  • Renal function should be measured before starting therapy and during therapy with canagliflozin, dapagliflozin, or empagliflozin.
  • The dose of these drugs should be reduced, or they should not be used at all if the patient has a specific level of renal impairment as measured by eGFR.
  • The presence of medical conditions or drugs that increase the risk of renal damage should be determined before initiation of therapy.
  • If the patient has a medical condition or is taking a drug that increase the risk of renal damage, kidney function should be closely monitored.
  • Therapy with the drug should be stopped if acute renal damage occurs.

Sulfonylureas: The sulfonylureas are not known to cause renal damage. Glimepiride and glipizide have a comparatively short duration of action and pharmacologically inactive metabolites, so these drugs are preferred for treating diabetic patients who have CKD;90,100 glyburide is not recommended in patients who have CKD.100The dose of sulfonylureas should be decreased if the patient has ESRD.

Thiazolidinediones: Less than 1% of a dose of a thiazolidinedione is excreted by the kidneys, the presence of CKD does not increase the level of the drug or metabolites,100,106 and the prescribing information for pioglitazone and rosiglitazone does not recommend using lower doses or decreasing the dose in patients who have impaired renal function.106 However, edema and fluid retention can affect 3%-5% of patients taking a thiazolidinedione106 (somewhat higher in patients taking insulin), and fluid retention in the context of CKD is potentially problematic.

Insulin: Most of a dose of exogenous insulin is metabolized by the kidneys and insulins are excreted in the urine.107 Prescribing information for insulins does not provide specific dosing recommendations, but it does state that because of these pharmacokinetic issues the dose may need to be decreased in a patient who has impaired renal function.

Pramlintide: Pramlintide is primarily metabolized by the kidneys, and it is excreted by the urine. The prescribing information for Symlin notes that patients with moderate to severe renal impairment (CrCl > 20 mL/minute - ≤ 50 mL/minute) did not have an increase in exposure or excretion of the drug, but that Symlin had not been studied in patients who require hemodialysis.

Weight Gain

Insulin, sulfonylureas, and thiazolidinediones can increase body weight;62,63 the other diabetic drugs may cause weight loss or have no effect on body weight.62,63

For patients who have not attained glycemic control with metformin and who do not have established ASCVD or CKD and for whom there is a compelling need to lose weight, the ADA recommends using a GLP-1 receptor agonist or an SGLT2 inhibitor.25

Specific Concerns of Diabetic Medications

α-glucosidase inhibitors: The prescribing information for Precose states that elevated serum transaminases two to three times the upper normal limit have occurred in up to 14% of all patients taking the drug and that Precose is contraindicated in patients who have cirrhosis. Subsequent clinical experience has shown that the elevations of serum transaminases are less common (2%-3%), they are dose-related, and in almost every case the patients were asymptomatic, and within a short period of time, the transaminases elevations reversed and returned to normal.108 Serious liver injury like fulminant hepatitis has occurred during therapy with acarbose, but this is a rare adverse effect.108 Serum transaminase elevations caused by miglitol are no more common than in patients taking a placebo, and no cases of acute or chronic liver injury caused by/associated with miglitol have been reported.109

DPP-IV inhibitors: The DPP-IV inhibitors have been associated with arthralgia, bullous pemphigoid, and pancreatitis.78

  • The risk for developing arthralgia is considered to be slight but statistically significant (a 1.44-fold increase), serious arthralgia is uncommon,110 and the pain should resolve within a month of discontinuing use of the drug.78 This adverse effect can occur within days of starting therapy with the drug or after several months78, and the duration of the patient’s diabetes may increase the risk of developing arthralgia.110
  • Bullous pemphigoid is an autoimmune dermal condition characterized by pruritis and blistering skin lesions, typically on the extremities, the trunk and occasionally on mucosal surfaces. Bullous pemphigoid is a rare adverse effect of the DPP-IV inhibitors, 111 the onset has been reported to be on average six months after starting therapy with a DPP-IV inhibitor, and in most cases, the condition resolves when the patient stops taking the drug.111
  • The prescribing information for alogliptin, saxagliptin, linagliptin, and sitagliptin states that cases of acute pancreatitis have been reported with their use, and research and clinical studies have confirmed this.78,112,113 However, the findings from the published literature are contradictory; some authors have concluded that DPP-IV inhibitors significantly increase the risk of developing pancreatitis, others have not,112,113 and a clear and unequivocal causal relationship between DPP-IV inhibitors and acute pancreatitis has not been established.78

SGLT2 inhibitors: The SGLT2 inhibitors have been associated with amputations, bone fractures, diabetic ketoacidosis, Fournier’s gangrene and genitourinary tract infections, and hypotension.104

  • The canagliflozin prescribing information has a US Boxed Warning stating that in two large randomized, placebo-controlled trials (CANVAS and CANVAS-R) involving patients with type 2 diabetes who did not have CVD or were not at risk for CVD, an approximately two-fold risk of lower limb amputation was observed. Analyses of those trials and of other research have not unequivocally confirmed or disproved this risk,114,115 and this is likely due to differing study designs. The mechanism of action that (may) cause lower limb amputation is not known. A class warning about amputation is mandatory for the prescribing information of the other SGLT2 inhibitors, but there is no evidence that the use of dapagliflozin empagliflozin, and ertugliflozin increases the risk of lower limb amputation.114
  • Bone fractures: The SGLT2 inhibitor prescribing warns that the use of these drugs may increase the risk for fractures; the genesis of this warning was information from the CANVAS trial. However, this trial included patients who were older, who had pre-existing risk factors for fractures, a relatively long duration of diabetes, and impaired renal function,116 and although the SGLT2 inhibitors may increase the risk for fractures and/or decrease bone density,104 current research has not found that canagliflozin or the other drugs of this class increase the risk for fractures.116,117
  • Diabetic ketoacidosis: The SGLT2 inhibitors can increase serum keto acids and glucagon production, and because of these effects, euglycemic diabetic ketoacidosis (DKA) can occur in patients who have type 1 diabetes or type 2 diabetes who are using one of these drugs.118,119 The FDA issued a warning about the SGLT2 inhibitors and DKA and the prescribing information for these drugs advises clinicians of the risk, but DKA is a very uncommon adverse effect of the SGLT2 inhibitors,118,119 and it is most likely to occur with off-label use of the drugs in patients who have type 1 diabetes or in patients who have risk factors like starvation.119
  • Fournier’s gangrene and genitourinary tract infections: Fournier’s gangrene, a severe, necrotizing infection of the genitourinary, perianal, and perineal areas that is difficult to treat and has a reported mortality rate of 16%.120 The use of SGLT2 inhibitors significantly (three-fold) increases the risk of genital tract infections.121 These infections are usually mild, they can be prevented and treated with good perineal care and standard therapy, and they are seldom severe enough that therapy with the drug needs to be stopped.122,123
  • Hypotension: The SGLT2 inhibitors cause an osmotic diuresis and susceptible patients may become hypotensive, e.g., patients who are taking an ACE inhibitor or a diuretic. Fortunately, hypotension caused by SGLT2 inhibitors is not a common adverse effect.122

Thiazolidinediones:

  • Fractures: Type 2 diabetes is associated with an increased risk for fractures, and there is evidence suggesting that the thiazolidinediones decrease bone density and are themselves an additional risk factor for fractures especially in women.124,125 The mechanism of action for these adverse effects is unknown, and there is no conclusive data that proves pioglitazone and rosiglitazone have adverse skeletal effects. The prescribing information for both drugs simply says that the risk of fracture should be considered and that current standards of assessment and maintenance of bone health should be followed.

Case Study # 1

A 47-year-old male with no significant PMH visits his primary care physician because he has been experiencing fatigue, dizziness, and lack of energy. These symptoms started approximately four months ago, initially intermittent and mild in nature but worsening in intensity and frequency the week prior to his visit. He cannot attribute their occurrence to any activity or time of day. He does report that his father had diabetes. The patient’s blood pressure is 162/88, and his weight is 118 kg, classifying him for his height as obese, and he smokes. His serum cholesterol is 280 mg/dL, he has elevated triglycerides, his fasting serum glucose is 225 mg/dL, and his HbA1C is 9.9%. There is no evidence on exam or by laboratory testing of retinopathy, nephropathy, or neuropathy. The physician tells the patient he has type 2 diabetes, advises lifestyle alterations (low-fat diet, exercise, smoking cessation, and weight loss) and prescribes metformin, 500mg PO, twice a day, and lisinopril, 20 mg, PO, once a day. The metformin dose is gradually increased to 850 mg PO, twice a day. The patient has some nausea and what he describes as “stomach upset” but after three weeks of taking metformin the gastrointestinal distress subsides. However, after three months of treatment, his fasting serum blood sugar is 189 mg/dL, and his HbA1C is 8.3%. Glipizide, 5mg PO, once a day is started. The patient rededicates himself to losing weight and exercising and three months later he has lost 12 kg. His fasting serum glucose is 140 mg/dL, and his HbA1C is 7.4%. The physician advises the patient that he has made good progress but that he needs to continue with the treatment regimen as there is a risk diabetes will worsen and that the onset of diabetic complications may have already begun.

Case Study # 2

A 58-year-old female with a PMH of type 2 diabetes and HTN is currently taking metformin, 1000 mg PO, twice a day, repaglinide 1 mg before each meal, and amlodipine. She visits her primary care physician to see the APRN for a checkup, and it is noted that her fasting serum glucose is 276 mg/dL, her HbA1C is 8.9%, her serum creatinine is 2.3 mg/dL, and her blood pressure is 172/88. Six months ago, her HbA1c had been 8.4%, and her fasting glucose was 234 mg/dL; six months prior to that her HbA1c had been 8.0%, and her fasting glucose had been 222 mg/dL. There is no evidence on physical exam or by laboratory studies that the patient has retinopathy or neuropathy. The patient has not lost weight, and she admits that she is not 100% compliant with her medication regimen. The APRN is concerned that after a year of therapy the patient has not reached her glycemic goals. He would like to prescribe insulin because he feels that the patient needs more aggressive lowering of blood glucose and HbA1c, but he is worried that her compliance with self-injecting insulin will be very poor. The APRN advises the patient that she has evidence of kidney damage and that she is at risk for other complications. He arranges a consultation with a Certified Diabetes Educator and adjusts the ant-hypertensive regimen. The Educator sets up several intensive information/education sessions with the patient. The patient quickly learns the techniques of self-injection, but she is very reluctant to use insulin as she feels “it is just too complicated for her.” The Educator arranges for frequent follow-up sessions that focus more on emotional support and encouragement than on technique. After three months of using basal and pre-prandial insulin, the patient’s HbA1c is 7.4%, and her fasting glucose is 151 mg/dL.

Conclusion

Glycemic control, prevention of diabetic complications, and slowing the progression of the disease requires the use of insulin for type 1 diabetics and a combination of oral anti-hyperglycemics and eventually, insulin for most patients who have type 2 diabetes. Patients who have diabetes almost without exception must take diabetic medications, and there is evidence that nurses’ knowledge of oral and injectable diabetic medications is often incomplete and insufficient.126,127 Key learning points for the safe use of the anti-hyperglycemics are:

  • Each anti-hyperglycemic medication has a specific mechanism of action and understanding how diabetic medications work is essential for using them safely. These mechanisms of action are:
    • Providing an exogenous source of insulin
    • Stimulating insulin secretion and release
    • Increasing insulin sensitivity
    • Decreasing glucagon secretion and glycogenolysis
    • Increasing renal excretion of glucose
    • Decreasing/delaying gastric absorption of glucose
  • The anti-hypoglycemics differ in terms of risk for hypoglycemia and risk for weight gain, effectiveness in the level of glucose control, and the adverse effects.
  • Areas of concern when using diabetic medications include the risk for hypoglycemia; potential for weight gain; the need for dosing adjustments in patients who have renal impairment; the potential for causing and/or exacerbating CVD or CHF; the effects these drugs have on the patient’s lipid profile, and; adverse effects that are specific to each drug like fractures in the thiazolidinediones, amputations with the DPP-IV agonists, and lactic acidosis with metformin.
  • The choice of which drug to use (aside from insulin for patients who have type 1 diabetes) will depend on many factors, e.g., age, co-morbidities.
  • Type 1 diabetics must use insulin.
  • Metformin is the first-choice drug for treating type 2 diabetes.
  • Basal insulin, GLP-1 receptor agonists, DDP-4 inhibitors, SGLT2 inhibitors, sulfonylureas, or thiazolidinediones are considered second-line drugs. α-glucosidase inhibitors, bromocriptine, colesevelam, and pramlintide can be considered third-line drugs.
  • There are no unequivocal guidelines regarding which second- and third-line drugs should be used and in what order if metformin is not successful. Most patients who have type 2 diabetes will need to use metformin and a second or third drug.
  • Many patients who have type 2 diabetes will eventually need to use insulin. There is strong evidence that early administration of insulin can preserve pancreatic β-cell function and positively influence the course of type 2 diabetes.

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