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Diabetic Medications

3.00 Contact Hours:
A score of 80% correct answers on a test is required to successfully complete any course and attain a certificate of completion.
Author:    Dana Bartlett (BS, MS, MA)

Purpose/Goals

This module will discuss the medications used to treat types 1 and 2 diabetes.

Approximately 12.3% of Americans have diabetes (Centers for Disease Control and Prevention, 2014) and the incidence of the disease, particularly type 2 diabetes, is rapidly and steadily increasing. 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 safely administer anti-hyperglycemics medications.

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.

Objectives

When this module has been completed, the learner will be able to:

  1. Identify the basic mechanisms of action of the anti-hyperglycemics.
  2. Identify adverse effects of the anti-hyperglycemics.  
  3. Identify the injectable medications used to treat type 1 diabetes.
  4. Identify how insulin is used to treat diabetes.
  5. Discuss the issues regarding glycemic control in patients who have type 2 diabetes.

Introduction

The primary derangement of type 1 and type 2 diabetes is hyperglycemia, an elevated blood glucose caused by 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 the cause of the long-term complications of diabetes, ie, retinopathy, nephropathy, and nephropathy, and it is a contributing factor in the pathogenesis of cardiovascular disease in patients who have diabetes.

There is a positive relationship of the level and duration of hyperglycemia to the incidence of these microvascular and macro-vascular pathologies and in addition, the level and duration of hyperglycemia has a negative effect on the progression of diabetes. 

Achieving and  maintaining glycemic control is the most effective way of preventing the development of diabetic complications and slowing their progression, and it can be a powerful and positive influence on the progression of diabetes (Chew, Davis, Danis, et al, 2014; Fullerton, Jeitler, Seitz, et al, 2014; Perkovic, Heerspink, Chalmers, et al, 2013). Prevention of diabetes and non-pharmacological interventions treatment of diabetes (when possible) would be ideal, and life style changes such as exercise, smoking cessation, and weight loss can help control HbA1c and blood glucose.

But patients who have type 1 diabetes must use insulin and in actual practice the majority of patients who have type 2 diabetes cannot attain glycemic control without medications. The latter group of patients needs an anti-hyperglycemic medication (or several) to attain the desired levels of fasting glucose and HbA1c.   Almost every patient who has type 2 diabetes will need oral anti-hyperglycemic medications at the time of diagnosis or shortly thereafter and many type 2 diabetics eventually need insulin (McCulloch, 11/24/2014). 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.

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 particular 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 life style alterations (low-fat diet, exercise, smoking cessation, and weight loss) and prescribes metformin, 500mg PO, twice a day, and lisonopril, 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 and 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 to continue with the treatment regimen as there is a risk the 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 makes adjustments to 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.

Medications Used to Treat Diabetes

Insulin

Mechanism of action: Insulin binds with insulin receptors on cell membranes. 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, and; 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.

Rapid-Acting: Insulin lispro (Humalog): Onset of action, 0.25-0.5 h; peak glycemic effect, 0.5-2.5 h; duration, ≤ 5 h. Insulin aspart (Novolog): Onset of action, 0.2-0.3 h; peak glycemic effect, 1-3 h; duration of action, 3-5 h. (Note: Humalog and Novolog are brand names for essentially the same drug).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: Insulin, regular: Onset of action, 0.5 h; peak glycemic effect, 2.5-5 h; duration, 4-12 h. Humulin R, Novolin R: Onset of action, 0.5 h; peak glycemic effect, 2.5-5 hour; duration, 4-12 h, 24 h for U-500 preparations. (Note: Humulin and Novolin are brand names for essentially the same drug)

Intermediate-Acting: Insulin NPH: Onset of action, 1-2 h; peak glycemic effect, 4-12 h; duration, 14-24 h. Humulin N, Novolin N: Onset of action, 1-2 h; peak glycemic effect, 4-12 h; duration, 14-24 h.

Intermediate to Long-Acting: Insulin detemir (Levemir): Onset of action, 3-4 h; peak glycemic effect, 3-9 h; duration, 6-23 h, dose dependent,

Long-Acting: Insulin glargine (Lantus): Onset of action, 3-4 h; there is no peak glycemic effect; Duration of action, ~ 11 to > 24 h.

Combination Products: Insulin aspart protamine suspension and insulin aspart (Novolog Mix 70/30: Onset of action, 0.17-33 h; peak glycemic effect, 1-4 h; duration of action, 18-24 h. Insulin lispro protamine and insulin lispro (Humalog Mix 75/25): Onset of action, 0.25-0.5 h; peak glycemic effect, 1-6.5 h; duration, 14-24 h. Insulin NPH suspension and regular insulin: Onset of action, 0.5 h; Peak glycemic effect, 2-12 h; Duration, 18-24. Brand names are Novolin 70/30, and Humulin, 70/30:

Dosage: Insulin dosages are prescribed to meet the goals of therapy, eg, 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: Lipotrophy at the injection site, hypoglycemia.

Amylinomimetic

Available forms: Pramlinitide (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, and; 3) Acting as a centrally-mediated appetite suppressant.

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

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

Dosage:

  • Type 1 diabetes: 15 mcg given subcutaneously immediately before a major meal. 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.
  • Type 2 diabetes; 60 mcg given subcutaneously immediately before a major meal 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: Anorexia, headache, hypoglycemia, nausea, post-prandial hypoglycemia, vomiting.

GLP-1 receptor agonists

Available forms: Albiglutide (Tanzeum), dulaglutide (Trulicity). Exenatide (Byetta), liraglutide (Victoza)

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. Albiglutide, dulaglutide, exenatide and liraglutide are GLP-1 receptor agonists. They bind to and activate GLP-1 receptors on the pancreatic β cells and as with human incretin, this action 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.

 Pharmacokinetics: Exenatide, time to peak plasma level, immediate release formulation, 2.1 hours. In most people exenatide concentrations are measurable for ~ 10 hour post-injection. Liraglutide, time to peak plasma level, 8-12 hours.

Dosage: These drugs should be injected subcutaneously

  1. Albiglutide: The starting dosage is 30 mg once a week. The dosage may be increased to 50 mg once weekly if needed.
  2. Dulaglutide: The starting dosage is 0.75 mg once a week. The dosage may be increased to 1.5 mg a week if needed.
  3. Exenatide: The immediate release formulation is given twice daily, 5 mcg, 60 minutes before a meal. The dosage can be increased to 10 mcg twice a day after 1 month if 5 mcg is not effective. The extended release formulation dosage is 2 mg given once a week.
  4. Liraglutide: 0.6 mg, subcutaneously, once a day for one week. After one week increase the dosage to 1.2 mg a day. The dosage can be increased to 1.8 mg a day if needed.

Contraindications: Hypersensitivity to the drug or to any component of the product, medullary thyroid cancer. These drugs should be used with caution in patients who have chronic kidney disease (Note: This will be discussed in greater detail later in the module).

Adverse effects: Constipation, diarrhea, headache, injection site pain, nausea, and vomiting.

Inhaled Anti-Hyperglycemics

Available Forms: 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.

Pharmacokinetics: The peak effect is ~ 53 minutes and the duration of action is ~ 160-180 minutes.

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, eg, 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 or 8 units that are inserted into a hand-held inhaler.

Contraindications: Hypersensitivity to regular insulin or to any component of the product, chronic lung disease such as asthma or COPD.

Adverse effects: Cough, hypoglycemia.

Oral Anti-Hyperglycemics

The oral anti-hyperglycemics are separated and discussed on the basis of their mechanisms of action.

a-glucosidase inhibitors

Available forms: Acarbose (Precose) and 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 and post-prandial glucose is lowered.

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

Pharmacokinetics: The time to peak plasma is 2-3 hours for acarbose and miglitol.

Dosage:

  1. Acarbose: The starting dosage 25 mg, three times a day, taken at the beginning of each meal. The maintenance dosage should be increased at 4-8 week interval and be adjusted based on the 1 hour post-prandial blood glucose and patient tolerance. 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: The starting dosage is 25 mg, three times a day, taken at the beginning of each meal. After 4-8 weeks the dosage can be increased to 50 mg three times. 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, inflammatory bowel disease, intestinal obstruction or a pre-disposition to intestinal obstruction, chronic intestinal diseases that interfere with absorption or digestion, or conditions that may deteriorate as a result of increased gas formation in the intestinal tract. The α-glucosidase inhibitors are contraindicated in patients who have a serum creatinine > 2 mg/dL.

Adverse effects: Abdominal pain, diarrhea, and flatulence: these effects tend to diminish with time. When the α-glucosidase inhibitors are used in combination with metformin, gastrointestinal side effects are more likely.

Biguanides

Available forms: Metformin is the only available biguanide.

Mechanism of action: Metformin decreases hepatic glucose production; decreases the intestinal absorption of glucose, and; 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 sufficient 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.

Dosage: The initial dosage is 500-100 mg a day. The dosage can be titrated in increments of 500 mg (With 1 week between dosage adjustments) up to a maximum of 2250 mg a day of the immediate release formulation and 2550 mg a day of the extended release formulation.

Contraindications: Hypersensitivity to the drug or to any component of the product. Renal disease with a serum creatinine > 1.4 mg/dL in females, > 1.5 mg/dL in males. Renal disease with a GFR < 30 mL/minute/1.73m2. The use of metformin should be temporarily discontinued in patients who will be receiving IV iodinated contrast dye. (Note: The use of metformin for patients who have renal disease will be covered later in the module)

Adverse reactions: Diarrhea, nausea, vomiting, impaired B12 absorption, and B12 deficiency. Lactic acidosis (Rare).

Bile acid sequestrants

Available forms: Colesevelam (Lodalis).

Mechanism of action: The mechanism by which colesevelam lowers blood glucose has not been identified.

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.

Contraindications: Hypersensitivity to colesevelam or to any component of the product, history of bowel obstruction, triglyceride level > 500 mg/dL, or hypertriglyceridemia-induced pancreatitis.

Adverse effects: Constipation, dyspepsia, flatulence. 

Dipeptidyl peptidase IV (DPP- IV) inhibitors

Available forms: Alogliptin (Nesina) linagliptin (Tradjenta), Saxigliptin (Onglyza), sitagliptin (Januvia).

Mechanism of action: Dipeptidyl peptidase IV is a protein 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.  

Dosages:

  • Alogliptin:  25 mg a day.
  • Linagliptin: 5 mg a day.
  • Saxigliptin: 2.5-5 mg a day.
  • Sitagliptin: 100 mg a day.

Contraindications: Hypersensitivity to the drug or to any component of the product. Diabetic ketoacidosis.

Adverse effects: Back pain, headache, naso-pharyngitis, and upper respiratory tract infections. Acute pancreatitis has been reported.

Dopamine receptor agonists

Available forms: Bromocriptine (Cycloset).

Mechanism of action: The mechanism of action of bromocriptine that lowers blood glucose has not been identified.

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.

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: Constipation, dizziness, fatigue, headache, nausea, rhinitis, weakness

Meglinitide analogs

Available forms: Nateglinide (Starlix) repaglinide (Prandin).

Mechanism of action: The meglinitide analogs increase calcium movement through calcium ion channels in the pancreatic β cells. The increase in intra-cellular calcium stimulates release of insulin.

Indications for 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.

Dosages:

  • Nateglinide: The initial dosage and the maintenance dose are the same: 120 mg, 3 times a day, 1-30 minutes before a meal. Patients who are close to their HbA1c goal should be started at 60 mg 3 times a day.
  • Repaglinide: Patients not previously treated or whose HbA1c is <8%: 0.5 mg before each meal.
  • Patients previously treated with anti-hyperglycemics whose HbA1c is ≥8%: 1 or 2 mg before each meal.
  • Dosing adjustments are determined by the blood glucose response, usually fasting blood glucose. Double the pre-prandial dose up to 4 mg until satisfactory blood glucose response is achieved. There should be at least 1 week between dosage adjustments. .
  • Dosage range: 0.5-4 mg, with meals. Repaglinide may be dosed pre-prandially 2-4 times a day in response to changes in the patient's meal pattern. Maximum recommended daily dose: 16 mg.

Contraindications: Hypersensitivity to the drug or to any component of the product, diabetic ketoacidosis, type 1 diabetes. Concurrent treatment with gemfibrozil (Repaglinide).

Adverse effects: Constipation, headache, upper respiratory infection. Repaglinide may cause symptomatic hypoglycemia.

Sodium-glucose co-transporter type 2 inhibitors

Available forms: Canagliflozin (Invokana), dapagliflozin (Fraxiga), empagliflozin (Jardiance).

Mechanism of action: Sodium-glucose co-transporter type 2 (SGLT2) is a glucose transporter that is found in the renal tubules. The 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.

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

Dosage:

  • Canagliflozin: The starting dosage is 100 mg a day, taken before the first meal. The maximum daily dosage is 300 mg; this can be used only if the patient has a GFR ≥ 60 mL/minute/1.73 m2.
  • Dapagliflozin: The starting dosage is 5 mg a day, taken in the morning; this can be increased to 10 mg a day.
  • Empaglifozin: The starting dosage is 10 mg a day; this may be increased to 25 mg a day.

Contraindications: Hypersensitivity to the drug or to any component of the product.  Diabetic ketoacidosis, 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.

Adverse effects: Decreased body weight, decrease in systolic blood pressure, mycotic infections, urinary tract infections. Canagliflozin may cause hyperkalemia.  

Sulfonylureas

Available forms: Chlorpropamide, glimepiride, glipizide, glyburide, tolbutamide, and 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:

  • Glimepiride: Peak effect, 2-3 hours. Duration, 24 hours.
  • Glipizide: Duration, 12-24 hours.
  • Glyburide: Duration, 12-24 hours.

Dosage:

  • Glimepiride: The initial dosage is 1-2 mg a day, taken in the morning. The dosage may be increased by 1-2 mg every 1-2 weeks if needed. The maximum daily dosage is 8 mg.
  • Glipizide: The dosage for the immediate release formulation is 5 mg a day, taken in the morning. This can be increased by 2.5-5 mg a day, no more than every several days. The maximum once a day dose is 15 mg. The maximum divided daily dose is 40 mg. The extended release formulation is started at 5 mg a day and the maximum daily dosage is 20 mg.
  • Glyburide: The initial dosage is 2.5-5 mg a day, taken in the morning. Lower starting dosages can be used if the patient if sensitive to anti-hyperglycemic drugs. 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. Use in patients who have type 1 diabetes mellitus or who have diabetic ketoacidosis. Concomitant use with bosentan (Glyburide). Glyburide is not recommended for use in older adults.

Adverse effects: Gastrointestinal distress and weight gain. The incidence of hypoglycemia has been reported to be is <3% for glipizide, 17% for glyburide, and 5%-20% for glimepiride.

Thiazolidinediones

Available forms: Pioglitazone (Actos), rosaglitazone (Avandia).

Mechanism of action: The thiazolidinediones lower blood glucose by a number 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.

Dosage:

  • Pioglitazone: 15-30 mg a day. 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. Patients should be observed closely for signs/symptoms of heart failure when the dosage is being increased. Patients who have CHF should receive no more than 15 mg a day.
  • Rosaglitazone: 4 mg a day in a single dose or in divided doses, twice a day. The dosage can be increased in 8-12 weeks if needed to a maximum of 8 mg. Rosaglitazone should be started at the lowest dose.
  • If insulin or a sulfonylurea is being used, the doses of these should be lowered if the patient is to be prescribed a thiazolidinedione. This is a consideration for other anti-hyperglycemics, as well.

Contraindications: Hypersensitivity to the drug or to any component of the product. Class III or IV heart failure.

Adverse effects: Edema and weight gain. Fractures, especially in women. The thiazolidinediones may cause or exacerbate heart failure.

Type 1 Diabetes

Patients who have type 1 diabetes depend on exogenous insulin to survive. Insulin therapy must be started at the time of diagnosis and can never be stopped.

Blood Glucose Monitoring

Blood glucose monitoring can be done at scheduled times during the day or by using a continuous glucose monitor. Continuous glucose monitoring offers the advantage of lower HbA1c levels and a lower risk of hypoglycemia. (Tumminia, Crimi, Sciacca, et al, 2015).

Insulin Therapy

The insulin therapy that is currently recommended is intended to mimic as closely as possible the normal physiological profile of insulin secretion and release (American Diabetes Association, 2015; McCulloch, 01/08/ 2015). This approach was initially called intensive insulin therapy to distinguish it from the traditional method of using insulin. It is now called multiple dose injections (MDI), and it is considered to be the standard of care. The traditional/conventional approach to insulin therapy is unlikely to achieve the target HbA1c level in patients who have type 1 diabetes or achieve optimal glycemic control for patients who have type 2 diabetes as their pancreatic β-cell function worsens (McCulloch, 02/06/2015). The basic principles of MDI are:  

  • Basal insulin: The patient is instructed to use an intermediate-acting or a long-acting insulin once or twice a day. This provides a basal level of insulin. The patient can also use an insulin pump that delivers a continuous infusion of a rapid-acting or a short-acting insulin.
  • Prandial insulin: The patient is instructed to use a short-acting or rapid-acting insulin before each meal. The amount of insulin will be determined by the pre-meal blood glucose, anticipated physical activity, and the amount of carbohydrate that will be ingested.

When compared to traditional insulin therapy this approach has been clearly shown to provide better glycemic control than the traditional approach and to significantly reduce the incidence of diabetic neuropathy, diabetic nephropathy, and diabetic retinopathy, albeit with a higher risk of severe hypoglycemic episodes (Nathan, Cleary, Backlund, et al, 2005; Diabetes Control and Complications Research Group, 1993).

Initiating insulin therapy for patients who have type 1 diabetes must be done on a case-by-case basis and the details of this will not be covered here. Specific issues regarding insulin therapy are discussed later in this module.

Glycemic control is the goal of treatment for diabetes and there are levels of blood glucose and HbA1c that are considered optimal. The goal of insulin therapy is an HbA1c of < 7%. However, not all patients can reach these goals and drug therapy for the treatment of diabetes must be prescribed with consideration of the patient’s age, co-morbidities, the duration of their disease, the benefits and risks of each drug (As they apply to the patient), and the likelihood that the patient can attain treatment goals (Inzzuchi, Bergenstal, Buse, et al, 2015; Ross, 2013).

Glycemic Goals

Glycemic control is the goal of treatment for diabetes and there are levels of blood glucose and HbA1c that are considered optimal. However, not all patients can reach these goals and drug therapy for the treatment of diabetes must be prescribed with consideration of the patient’s age, co-morbidities, the duration of their disease, the benefits and risks of each drug (As they apply to the patient), and the likelihood that the patient can attain treatment goals (Inzzuchi, Bergenstal, Buse, et al, 2015; Ross, 2013).

Human Insulin Versus Insulin Analogs

The first insulins were derived from animal pancreas. These were replaced by synthetic human insulins that did not pose the risk of allergic reactions associated with animal-derived insulins. Human insulins (NPH and regular insulin) are still manufactured and used but they do not produce a time to peak effect and duration of action that replicates that of physiological insulin and the insulin analogs are now preferred (American Diabetes Association, 2015; McCulloch, 01/08/ 2015).

The insulin analogs that are used for pre-prandial injections have a more rapid onset of action and a shorter duration of action than regular insulin, and the intermediate-acting and the long-acting insulin analogs have a longer duration of action and a more constant effect than NPH. These changes in pharmacokinetics produce insulin levels that more closely resemble normal insulin secretion and release. The rapid-acting and short-acting insulin analogs can be injected much sooner before a meal, allowing for more effective dosing, and they are less likely than regular insulin to cause hypoglycemia in patients who have type 1 diabetes: this may be true of the long-acting analogs as well (McCulloch, 01/08/ 2015).

Insulin Pump

An insulin pump delivers a continuous infusion of a rapid-acting insulin (aspart, glulisine, or lispro) that provides the patient with a basal insulin level and the patient uses a pre-prandial dose of a short-acting insulin as needed. Short-acting insulins can be used, but rapid-acting preparations are preferred (McCulloch, 01/08/2015). The prescribed dosage is typically 40%-60% of the total daily dose that would be used for MDI, and the pre-prandial doses are determined by the blood glucose level immediately before the meal and the carbohydrate content of the meal (McCulloch, 01/08/2015).

Patient preference is usually the deciding factor when choosing between MDI and a continuous insulin infusion pump. Adults who have type 1 diabetes may have better glycemic control with a continuous infusion pump but for most patients there is no significant difference between the two methods in terms of glycemic control or  the incidence of hypoglycemic episodes (McCulloch, 01/08/2015; Yeh, Brown, Maruthur, et al, 2012; Golden, Sapir, 2012). The insulin pump does provide a more consistent absorption of the insulin, and there are pumps that can be used in conjunction with a continuous glucose monitoring (CGM) device and these sensor-augmented pumps have been proven to be successful (Bergenstal, Tamborlane, Ahmann, et al, 2010). The use of an insulin pump may be advantageous if the glycemic goal cannot be attained with MDI (Tumminia, Crimi, Sciacca, et al, 2015). Insulin pumps are more expensive than using syringes and vials, and some patients find implantation of the pump awkward or embarrassing. Also, given that the dose of insulin delivered is relatively small any interruption in flow or a malfunction of the pump can potentially cause a rapid onset of hypoglycemia or diabetic ketoacidosis (McCulloch, 01/08/205).

Insulin Pens

Insulin pens have many advantages. They are preferred by most patients for convenience and ease of use (Ahmann, Szeinbach, Gill, et al, 2014; Segggelke, Hawkins, Gibbs, et al, 2014); they are least as effective as syringes and vials in attaining glycemic control (Segggelke, Hawkins. Gibbs, et al, 2014; Xie, Zhou, Wei, et al, 2014); patient adherence to insulin therapy is better with an insulin pen than it is with syringes and vials (Xie, Zhou, Wei, et al, 2014; Grabner, Chu, Raparla, et al, 2013), and; they are more accurate when delivering small doses (Cuddihy, Borgman, 2013; Luijf, DeVries, 2010). The incidence of hypoglycemia associated with the use of an insulin pen, when compared to syringes and vials, has been reported to be lower (Davis, Wei, Garg, 2011) or equivalent (Ahmann, Szeinbach, Gill, et al, 2014; Lee, Li, Reynolds, et al, 2011).

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 (McCulloch, 02/06/ 2015; Binder, Lauritzen, Pramming, 1984). 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 (Hansen, Matytsina, 2011).  

Intramuscular injection: Inadvertent intramuscular injection of insulin causes rapid and irregular absorption (Hansen, Matytsina, 2011). 

Needle size: Studies have shown that using needle sizes of 4 mm, 5 mm, 6 mm, or 8 mm did not significantly affect insulin absorption (de la Peña, Yeo, Linnebjerg, et al, 2015; Hirose, Ogihara, Tozakae, 2013). Research indicates that the average skin thickness is adults is 2.88 mm (Kreugel, Keers, Kerstens, et al, 2011) so 4 mm or 5 mm needles are suitable for insulin injections, even in patients who are obese (Kreugel, Keers, Kerstens, et al, 2011; Hirsch, Gibney, Albanese, et al, 2010).

Size of the dose: Increasing the amount of the dose slows absorption (McCulloch, 02/06/2015; Hansen, Matytsina, 2011; Binder, Lauritzen, Pramming, 1984). The use of U-500 insulin rather than the standard U-100 may be advised if patients must inject large volumes. 

Skin temperature and local blood flow: Higher skin temperature can increase the absorption of insulin (Sindleka, Heinemann, Berger, et al, 1994). Blood flow to the injection site also affects insulin absorption, and blood flow and insulin absorption can be influenced by the ambient temperature, recent exercise or massage of the injection site area, lipohypertrophy, and smoking (Mokta, Mokta, Panda, 2013; Seyoum , Abdulkadir, 1996; Hildebrandt, 1991; Binder, Lauritzen, Pramming, 1984). A pilot study in type 2 diabetics suggested that smoking can affect other aspects of insulin pharmacokinetics, eg, higher insulin concentrations and decreased insulin clearance (Bott, Shafagoj, Sawicki, et al, 2005).

Injection site: Studies indicate that there is little difference in the depth of subcutaneous tissue at the commonly used injections site (Hansen, Matytsina, 2011; Gibney, Arce, Byron, 2010), but there are variations in absorption at the different injection sites, eg, a greater degree of absorption and more rapid absorption in the abdomen than in the thigh (McCulloch, 02/06/2015; Trimble, Meneilly, 2014; Hansen, Matytsina, 2011; ter Braak, Woodworth, Bianchi, et al, 1996). This could influence the choice of injection site: the abdomen may be preferable for pre-prandial injections when a rapid rise in insulin level is desired (McCulloch, 02/06 2015).

Injection angle and technique: The angle of injection should be 90° unless the patient has a normal BMI and is using an 8 mm needle in which case a 45° angle should be used (Hansen, Matytsina, 2011). Using or not using a lifted skin fold technique will depend on the length of the needle, the patient’s BMI, and the injection location (Hansen, Matytsina, 2011). The needle should be left in place for 5-10 seconds after the injection to prevent backflow and/or leakage. (Wittman, Kover, Kralj, 2010; Becton-Dickinson).

Self-injection of insulin is not complicated, but newly diagnosed type 1 diabetics will need to be taught the proper techniques, ie, 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

 Multiple daily injections of insulin decrease the onset and incidence of the microvascular complications of diabetes, this technique appears to modestly lower mortality rate (Writing Group for the DCCT/EDIC Research Group, Orchard, Nathan, et al, 2015) and MDI is now the standard of care (American Diabetes Association, 2015).

However, the MDI approach has been shown to increase the risk of severe hypoglycemia (Fullerton, Jeitler, Seitz, 2014; DCCT Research Group, 1997), and the incidence of hypoglycemia in this patient population (Patients who have type 1 diabetes) is very high. At least one in six patients who have type 1 diabetes have at least one episode a year of severe hypoglycemia (Giorda, Ozzello, Gentile, et al, 2015). The follow-up to the DCCT trial showed that 65% of patients with type 1 diabetes had at least one episode a year of severe hypoglycemia (DCCT, 1997), and Unger (2012) noted that patients who have type 1 diabetes have symptomatic hypoglycemia on the average of twice a week.

Hypoglycemia increases morbidity and mortality (Giorda, Ozzello, Gentile, et al, 2015; Frier, 2014; Unger, 2012), and hypoglycemia is a significant cause of death in patients who have type 1 diabetes (Feltbower, Bodansky, Patterson, et al, 2008; Skrivarhaug, Bangstad, Stene, et al, 2006).

The problem is compounded as patients who have diabetes grow older (UK Hypoglycaemia Study Group, 2007) and as the frequency of hypoglycemic events increases. Recurrent hypoglycemia has a negative effect on the adrenomedullary, autonomic, hormonal, and sympathetic responses to hypoglycemia, and recurrent hypoglycemia can eventually cause an effect called hypoglycemia unawareness (Senior, Bellin, Alejandro, et al, 2015; Unger, 2012). Patients who have hypoglycemia unawareness do not have the expected and adaptive sign and symptoms of hypoglycemia, eg, confusion, diaphoresis dizziness, weakness are absent or blunted. The patient does not realize that the blood glucose is low and cannot self-treat or seek medical attention. As the hypoglycemic episodes increase in frequency and severity the hypoglycemia unawareness effect worsens, further increasing the number of hypoglycemic episodes and creating a dangerous cycle that can have fatal consequences.
 
Hypoglycemia Definitions (Alsahli, Gerich, 2013)

  • Severe hypoglycemia: Requires assistance of another person to administer carbohydrate, glucagon, or another resuscitative action. The neurologic recovery from restoring plasma glucose to normal is considered sufficient 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, the blood glucose is not measured but it is probably ≤ 70 mg/dL.
  • Pseudo-hypoglycemia:  An event during which the diabetic person has the typical symptoms of hypoglycemia with a measured plasma glucose > 70 mg/dL but approaching that level.

Patient Adherence to and Compliance

Sub-optimal adherence to and compliance with a prescribed insulin regimen are common in patients who have type 1 diabetes (Faraesi, Mania, Heydari, 2014; Peyrot, Barnett, Meneghini, et al, 2012). Faraesi, Mania, Heydari, 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 (Faraesi, Mania, Heydari, et al, 2014).

Pramlintide

At this time none of the oral anti-hyperglycemics are FDA approved for the treatment of type 1 diabetes. Pramlintide is the only other injectable anti-hyperglycemic that is FDA approved as a treatment for type 1 diabetes and it should only be used as an adjunctive therapy along with insulin.
 Pramilintide has been shown to produce a significant decrease in HbA1c when it is used as adjunctive therapy for patients who have type 1 diabetes (Ratner, Dickey, Fineman, et al, 2004; Whitehouse, Kruger, Fineman, et al, 2002) and the use of pramlintide does allow for using lower doses of insulin (McCulloch, 01/2015). However, pramlintide must be used carefully and with these caveats and restrictions in mind (Lexicomp®, 2015; McCulloch, 01/08/2015).

  • Pramlintide must be injected separately from insulin and at a different site.
  • Do not administer pramlintide in the arm: the absorption is not predictable.
  • Patients who have severe hypoglycemia unawareness or severe hypoglycemia should not use pramlintide.
  • When therapy with pramlintide is started, the pre-meal doses of insulin should be reduced by 50% and then titrated up to achieve euglycemia once the desired dose of pramlintide is reached.
  • The injection of pramlintide should be done immediately before a meal. 
  • If pramlintide is discontinued for any reason, restart therapy with the same initial titration protocol. If a dose is missed, wait until the next scheduled dose and administer the usual amount.

Type 2 Diabetes

Life style changes should be the first treatment for patients who have type 2 diabetes. Unfortunately, complete remission of type 2 diabetes is rare, even with intensive changes in diet and exercise patterns, and the number of patients who achieve partial remission through life style changes is disappointingly low (Gregg, Chen, Wagenknecht, et al, 2012).
 
A timely diagnosis and a lower initial lower initial HbA1c may increase the effectiveness of life style interventions, perhaps by preserving pancreatic β cell function (Gregg, Chen, Wagenknecht, et al 2012), and it has been proven that early control of hyperglycemia reduces the risk of the microvascular and (possibly) macro-vascular complications of type 2 diabetes (Lovre, Fonesca, 2015; McCulloch, 01/30/2015) and improves glycemic control in the future (Colagiuri, Cull, Colman, et al, 2002). But type 2 diabetes has a long latent phase and the metabolic abnormalities of diabetes worsen with time. Many patients who have type 2 diabetes are not diagnosed until many years after the onset of the disease (Lim, 2014; Simmons, Echouffo-Tcheugui, Sharp, et al, 2012) and the great majority of patients who have type 2 diabetes need medications to attain their glycemic goals (McCulloch, 01/30/2015)

Anti-Hyperglycemic Therapy

There are few studies that have directly compared the glucose lowering abilities of the oral anti-hyperglycemics and the reported differences between them in this respect appear to be small and/or not significant (Inzucchi, Bergenstal, Buse, et al, 2015; McCulloch, 01/30/2015; DeSai, Shrank, Fischer, et al, 2012). The choice of an oral anti-hyperglycemic for treating patients who have type 2 diabetes depends then on cost, safety profile, the potential for weight gain, co-morbidities, patient preference, and the risk of hypoglycemia associated with each particular medication.   

Starting Therapy

Unless there is a contraindication to its use, metformin is the drug of choice when starting treatment for patients who have type 2 diabetes (American Diabetes Association, 2015; Brietzke, 2015; McCulloch, 01/30/2015). There are many reasons why metformin is universally recommended as the first medication for newly diagnosed type 2 diabetics (American Diabetes Association, 2015; Inzucchi, Bergenstal, Buse, et al, 2015; McCulloch, 01/30/2015).

  • Considerable clinical experience with its use
  • Highly effective
  • Low cost
  • No risk of hypoglycemia when used as monotherapy
  • No weight gain
  • Possible protective effect in preventing cardiovascular complications
  • Very good safety profile

 Diarrhea and nausea are often seen in patients taking metformin but these effects typically subside after a few weeks of therapy (Brietzke, 2015). Malabsorption of vitamin B12 and B12 deficiency are common in patients taking metformin (Ko, Ko, Ahn, et al, 2014; Liu, Li, Quan, et al, 2014; Pierce, Chung, Black, 2012) and vitamin B12 deficiency has been reported in 5.8%-33% of all patients taking metformin (Kibirge, Mwebaze, 2013). Clinical neuropathy and anemia associated with vitamin B12 deficiency caused by metformin therapy have been reported, as well (Singh, Kumar, Karmakar, et al, 2013; Pierce, Chung, Black, 2012).There are no agreed upon guidelines regarding when and for whom B12 deficiency screening should be done, but it seems prudent to measure the B12 level prior to initiating metformin therapy and at 1-2 year intervals if the  patient is taking high doses of metformin or has been taking metformin for > 4 years (Beulens, Hart, Kujis, et al, 2015; Ko, Ko, Ahn, et al, 2014; Mazokopakis, Starakis, 2012).  
 
The use of metformin in patients who have kidney disease has been restricted and if the serum creatinine is above a certain level or if the GFR is below a certain level, the use of metformin is contraindicated. The concern has been that as metformin is excreted renally impaired renal function may cause accumulation of the drug and metformin-associated lactic acidosis, a rare but potentially deadly complication. Some authorities believe that the current restrictions on the use of metformin are unrealistic and are not supported by a large amount of good quality evidence, and that these restrictions prevent a large number of people from receiving the drug. A recent review of the literature noted that metformin does not accumulate in patients who have mild-to-moderate kidney disease (GFR 30-60 mL/min/1.73 m2) and that the “ . . .overall incidence of lactic acidosis in metformin users . . . is generally indistinguishable from the background rate in the overall population with diabetes.” (Inzucchi, Lipska, Mayo, et al, 2014). However, at this time there have been no changes in the prescribing restrictions for metformin.

Adjusting Therapy

If mono-therapy with metformin and life style changes do not produce the desired HbA1c  level within three months one of the six “second-line” anti-hyperglycemic drugs should be added to the regimen (American Diabetes Association, 2015; McCulloch, 01/30/2015; McCulloch, 10/29/2014 ). Also, if the patient has an initial HbA1c ≥ 9% at the time of diagnosis and is unlikely to achieve reach the desired level of glycemic control using only metformin, she/he can be started on dual-drug therapy using one of the following six medications (Inzucchi, Bergenstal, Buse, et al, 2015) 

  • Basal insulin
  • GLP-1 receptor agonist
  • DPP-4 inhibitor
  • SGLT2 inhibitor
  • Sulfonylurea
  • Thiazolidinedione

These medications (and others) can be used as the first-choice drug if metformin is contraindicated. As mentioned earlier the oral anti-hyperglycemics are all closely equivalent in terms of their abilities for lowering HbA1c. But compared to metformin there is much less clinical experience (Except with insulin) with these six medications for use as a first-line agent; the cost of these other drugs is higher; the risk of hypoglycemia, increase in weight, and negative cardiovascular outcomes is higher with insulin and the sulfonylureas than with metformin, and; the side effects they potentially can produce are more severe than those of metformin (Inzucchi, Bergenstal, Buse, et al, 2015; McCulloch, 01/30/2015, 2015; Azimova,  San Juan, Mukherjee, 2014; Desai, Shrank, Fischer, et al, 2012). These same concerns are also true of the α-clucosidase inhibitors, bromocriptine, colesevelam, and pramlintide, which are generally considered to be third-line medications (Inzucchi, Bergenstal, Buse, et al, 2015).

Third-Line Medications 

  • α-glucosidase inhibitors
  • Bromocriptine
  • Colesevelam
  • Pramlinitide

Any of the six second line medications can be added to the patient’s medication regimen. There are no definitive guidelines as to which one is preferable (Inzucchi, Bergenstal, Buse, et al, 2015) and there is little data comparing the possible combinations, ie, metformin and a GLP-1 receptor agonist versus metformin and a thiazolidinedione (American Diabetes Association, 2015). Also, if the patient cannot tolerate metformin there is no consensus on which combination of second-line and third-line drugs is the safest and most effective alternative (Goldman-Levine, 2015).
 
The decision as to which second-line medication should be used then depends on patient preference, co-morbidities, and the side effect profile of the medication. For example, some oral anti-hyperglycemics appear to decrease the risk of cardiovascular events while some may increase this risk (Singh, Bhat, Wang, 2013). If a second medication is unsuccessful a third can be added. The addition of a second medication is expected to lower the HbA1c by 1%-1.5% and the addition of a third drug is expected to lower the HbA1c by 0.5%-1% (Brietzke, 2015).

Predictors of Response to Oral Anti-Hyperglycemics

Factors that predict a response to treatment with oral anti-hyperglycemics drugs are listed below (Brietzke, 2015). If the patient has several of these, initial treatment with insulin may be necessary.
 
Predictors of Response to Oral Anti-Hyperglycemics 

  • Absence of symptoms, eg rapid weight loss, severe polydipsia/polyuria
  • Absence of fasting ketonuria
  • Fasting glucose < 250 mg/dL.
  • HbA1c < 10%
  • Newly diagnosed type 2 diabetes
  • Obesity

Specific Concerns about Second and Third Line Medications

α-glucosidase inhibitors: These drugs are considered less potent than metformin and the sulfonylureas for lowering Hb A1c (McCulloch, 12/13/2013). Acarbose and miglitol appear to be equivalent in ability to lower HbA1c, they are unlikely to cause hypoglycemia unless they are used in combination with another drug and they are weight neutral. Diarrhea and flatulence are very common side effects of the α-glucosidase inhibitors but they are dose-related and can be managed by starting the medication at the low end of the dosage range. There is some clinical experience with monotherapy with the α-glucosidase inhibitors, but the labeled use of these drugs is as an adjunctive treatment.

Elevated serum transaminases have occurred in up to 14% of patients in long-term studies of acarbose (Lexicomp®, 03/17/2015). This effect appears to be dose-related, more common in females, and reversible (Lexicomp®, 2015).

Acarbose and miglitol should not be used in patients who have significant renal impairment (Serum creatinine > 2 mg/dL) and should be used cautiously in patents who have renal impairment (Lexicomp®, 03/17/2015).

Bromocriptine: Bromocriptine produces a modest effect on HbA1c level; it does not cause hypoglycemia (American Diabetes Association, 2015; Grunberger, 2013). Serious adverse effects associated with bromocriptine are rarely reported (Ghosh, Sengupta, Sahana, et al, 2014; Defronzo, 2011). Dizziness, nausea, and vomiting are common but these are usually mild and transient (Defronzo, 2011; Gaziano, Cincotta, O’Connor, et al, 2010).  

Colesevelam: Colesevalam, when used with other oral agents or with insulin, has been shown to produce significant reductions in fasting glucose and HbA1c  (Brunetti, DeSantis, 2015; Oii, Loke, 2014). It does not cause hypoglycemia or serious adverse effects and it is weight neutral (American Diabetes Association, 2015; Brunetti, De Santis, 2015). There is some clinical experience using  monotherapy with colesevelam but its labeled use is as an adjunctive treatment

DPP-IV inhibitors: The DPP-IV inhibitors are considered less efficacious at lowering HbA1c than metformin or the sulfonylureas but they have a lower risk of adverse effects (And less serious adverse effects) than those drugs (Liu, Xiao, Zhang, et al, 2014; Wu, Li, Liu, 2014; Zhang, Hong, Chi, et al, 2014). Gastrointestinal side effects are possible but are typically mild and decrease after 3-4 weeks of therapy (Rigato, Fadnini, 2014) and the incidence of these effects is not high. The DDP-IV inhibitors are unlikely to cause hypoglycemia unless they are used in combination with another drug, and they are considered weight neutral. Concern has been expressed that the DPP-IV inhibitors can increase the risk for upper respiratory tract infections. At this time the evidence for this is inconclusive (Liu, Xaio, Zhang, et al, 2014), but patients should be cautioned to contact a healthcare provider if they have signs or symptoms of a cold or the flu. These drugs are renally excreted and dose reductions of the DDP-IV inhibitors are indicated in patients who have chronic kidney disease (Scheen, 2015).

GLP-1 receptor agonists:  The GLP-1 receptor agonists have all been shown to be effective at lowering HbA1c (Trujillo, Nufler, Ellis, 2015), albeit with slight differences between the drugs. Constipation, diarrhea, nausea, vomiting, and injection site pain are common side effects (Dungan, DeSantis, 2015; Harris, McCarty, 2015). The frequency and intensity of these adverse effects varies depending on the drug and the dosage, but they are seldom severe and the gastrointestinal effects usually diminish 4-8 weeks after starting therapy (Harris, McCarty, 2015). The GLP-receptor agonists are unlikely to cause hypoglycemia unless they are used in combination with another drug, and they can cause significant weight loss (Dungan, DeSantis, 2015; Trujillo, Nuffler, Ellis, 2015).

The GLP-1 receptor agonists should be used with caution in patients who have moderate to severe renal impairment (Giorda, Narda, Tartaglino, 2014), and dosing increases should be done slowly. The prescribing information for albiglutide, dulaglutide, exenatide, and liragluitide notes that: 1) There have been post-marketing reports of acute renal failure and worsening of chronic renal failure associated with the use of GLP-1 receptor agonists, and the majority of these events occurred in patients who have experienced dehydration, diarrhea, nausea, and vomiting; 2) Exenatide should not be used in patients who have ESRD or patients who have a GFR < 30 mL/minute/1.73m2, and; 3) Exenatide should be used cautiously in patients who have had a kidney transplant.

Meglinitide Analogs: Nateglinide and repgalinide can significantly lower HbA1c. Repaglinide has been shown to more effective in this respect and to have a greater effect than nateglinide on reducing fasting glucose (Guardado-Mendoza,  Prioletta, Jiménez-Ceja, et al, 2013). Repaglinide may cause symptomatic hypoglycemia (Severe hypoglycemia is rare) and the melglinitide analogs can cause a moderate increase in weight. (American Diabetes Association, 2015; Tran, Zielinksi, Roach, et al, 2015; Guardado-Mendoza,  Prioletta, Jiménez-Ceja, et al, 2013; Rosenstock, Hassman, Madder, et al, 2004).
Upper respiratory tract infection has been reported to occur in ~ 10% of all patients receiving nateglinide or repaglinide. Arthralgia, constipation, headache, sinusitis, and vomiting have been reported, as well, but the patterns of these adverse effects have not been detailed (Rosenstock, Hassman, Madder, et al, 2004). The prescribing information for natgelinide and repaglinide stress that these drugs should be used with caution in patients who have hepatic impairment, but no specific guidelines are offered.

Pramlintide: Pramlintide produces modest decreases in HbA1c and body weight (Grunberger, 2013). The most common side effects are anorexia, headache, and vomiting. These are usually dosage-dependent, mild to moderate in intensity, and diminish with time (Grunberger, 2013). Post-prandial hypoglycemia is possible.  

SGLT2 Inhibitors: The SLGT2 inhibitors offer the advantages of a moderate to significant decrease in HbA1c, a slight reduction in blood pressure, no risk of hypoglycemia unless there is concomitant use of a sulfonylurea or insulin, and a decrease in body weight (Vivian, 2014; McCulloch, 01/29/2014).

Canagliflozin can cause hyperkalemia in patients who have a GFR of 45 to < 60 mL/min/1.73m2 or in patients who are taking drugs that affect potassium excretion, eg, potassium-sparing diuretics or drugs that inhibit the rennin-angiotensin-aldosterone system (Vivian, 2104).

Genital and urinary tract infections, perhaps related to relatively high urinary glucose levels, are a common side effect of the SGLT2 inhibitors (Kalra, 2104; Lajara, 2014). These infections are usually mild and they can be prevented with good perineal care. They respond to standard therapies and they are seldom severe enough that therapy with the drug needs to be stopped (Kalra, 2014; Vivian, 2014).

Glucosuria and osmotic diuresis has the potential to cause orthostatic hypotension, but this is an uncommon effect of the SLGT2 inhibitors (Kalra, 2014). Regardless, the prescribing formation recommends that any fluid volume deficits be corrected before starting one of these drugs.

Sulfonylureas: The sulfonylureas were introduced in the early ‘80s and because the long duration of clinical experience with their use and their low cost they are one of the most prescribed anti-hyperglycemics. They are also very effective; on average the sulfonylureas can be expected to lower the HbA1c by 1.5% (Hirst, Farmer, Dyar, et al, 2013). The sulfonylureas will cause weight gain and because of their mechanism of action, hypoglycemia is not infrequent (Brietzke, 2015). Because of this risk of hypoglycemia the sunfonylureas should be used cautiously in the following patients/situations.

  • Elderly adults
  • Patients who are taking a beta-blocker.
  • Patients who have autonomic neuropathy.
  • Patients who are malnourished
  • Hepatic or renal impairment
  • With prolonged exercise or ethanol ingestion

Glyburide in particular is not recommended to be prescribed for older adults because of the risk for prolonged hypoglycemia (American Geriatrics Society, 2012)

Thiazolidinediones: The thiazolidinediones are effective at lowering HbA1c, alone or in combination with metformin or a sulfonylurea (Tran, Zielinksi, Roach, et al, 2015). They do not cause hypoglycemia unless used in combination with another drug but they can cause significant weight gain (Tran, Zielinksi, Roach, 2015). The use of these drugs is limited by the risks for fractures and congestive heart failure (CHF). Patients who have diabetes have an increased risk of developing osteoporosis and fractures. The thiazolidindiones reduce bone mineral density and when they are used for > 1 year it has been shown that there is an increased risk for distal extremity fractures, especially in women > 70 years of age (Betteridge, 2011; Riche, King, 2010).

The use of thiazolidinediones has also been consistently associated with a risk for developing CHF, with or without pre-existing left ventricular diastolic or systolic dysfunction (Hernandez, Usmani, Rajamanickam, et al, 2011; Lago, Singh, Nesto, 2007). These drugs should be used with caution in patients who have New York Heart Association class I or II CHF, and they are contraindicated if the patient has class III or class IV CHF (Tran, Zielinski, Roach, 2105).

New York Heart Association Functional Classification

  • Class I:  Cardiac disease, but no symptoms and no limitations in ordinary physical activity, eg, 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, eg, walking short distances (20-100 m). Comfortable only at rest.
  • Class IV: Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients

Insulin Therapy

The natural course of type 2 diabetes is characterized by a gradual decline in pancreatic β-cell function, slowly decreasing insulin sensitivity, a worsening of hyperglycemia, and a diminished responsiveness to oral anti-hyperglycemics over time (Li, Wang, Xiao, et al, 2015; McCulloch, 11/24/2014). Type 2 diabetes is a progressive disease and as many patients are diagnosed with type 2 diabetes years after the onset of the disease, the pathologic changes described above are well established when the disease is first noted (Hanfeld, 2014). Given these facts it is not surprising that the clinical course of many patients who have type 2 diabetes is typified by poor glycemic control and the need for multiple medications, and approximately 26% of patients who have type 2 diabetes use insulin (Wallia, Molitch, 2014).

Insulin is usually prescribed as second- or third-line drug for patients who have type 2 diabetes and have not attained the desired HBA1c. If, when the patient is first diagnosed with type 2 diabetes, the Hb A1c is > 10%, the fasting plasma glucose is > 250 mg/dL, a ransom glucose level is > 300 mg/dL, the patients has symptoms of hyperglycemia, ketonuria is present, or he/she has weight loss in association with hyperglycemia then insulin should be considered as a first-line drug (McCulloch, 11/24/2014; Wallia, Molitch, 2014).

There are numerous protocols for prescribing insulin for patients who have type 2 diabetes, and the differences between them are considered to be small (McCulloch, 11/24/2014). The basic approach is as follows (Wallia, Molitch, 2014):

  • Start by adding basal insulin, glargine or detemir in the morning or the evening.
  • The dose can be slowly increased every few days until the target level of fasting glucose is reached.
  • If the patient is taking a sulfonylurea or pioglitazone these should be stopped. DDP-IV inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors can be continued.
  • If after three months the HbA1c and fasting glucose target levels have not been reached, start pre-prandial insulin.

Insulin is usually prescribed after a trial of oral anti-hyperglycemics has failed, but it is possible that insulin should be one of the first drugs prescribed for patients who have type 2 diabetes. There is a considerable amount of evidence that suggests that early and intensive treatment with insulin can decrease the burden placed on the pancreatic β-cells, prevent loss of β-cell mass, and positively influence how type 2 diabetes progresses (Hanefeld, 2014; Li, Wang, Xiao, et al, 2014; Kramer, Zinman, Retnakaran, 2013; Weng, Li, Xu, et al, 2008). Studies have shown that when insulin therapy is started early in patients who have type 2 diabetes, patients have improved glycemic control, higher rates of remission, preservation of β- cell function, an improved response to insulin, and the incidence of diabetic complications is reduced (Hanefeld 2014; Li, Wang, Xiao, et al, 2014; Weng, Li, Xu, et al, 2008).   

Patient Issues

Many patients who have type 2 diabetes will eventually need insulin and early use of insulin has significant benefits. “Psychological insulin resistance” however is a very common phenomenon in patients who have diabetes and in physicians as well, the latter being described as “clinical inertia,” or “benign neglect.” (Edelman, Pettus, 2014; Ross, 2013; Harris, Ekoé, Zdanowicz, et al, 2005).

Patient fears of insulin include, but are not limited to: fear of needles; discomfort with a perceived complexity of insulin therapy; perception of insulin therapy as equivalent to “failure;” fear of side effects such as hypoglycemia; concern for costs, and; concern over weight gain (Ahmann, Szeinbach, Gill, et al, 2014; Edelman, Petttus, 2014; Ross, 2013). Physician barriers to initiating insulin therapy include over-caution regarding insulin therapy; fear of side effects, and; lack of time and resources for initiating and monitoring insulin therapy (Ross, 2013). Unfortunately, many physicians continue to prescribe oral anti-hyperglycemics well past the point they will be effective (Spollet, 2012).

The effects of patient resistance to insulin therapy and clinician failure to initiate insulin therapy are significant. Many patients who have type 2 diabetes do not reach the target goals of glycemic control (Sorli, Heile, 2014; Ross, 2013), and initiation of insulin therapy often begins when HbA1c levels are high, eg, 9%-10% (Khunti, Danci, Meneghini, et al, 2012) and/or up to 11 years after the initial diagnosis (Goodall, Sarpong, Hayes, et al, 2009). Sorli and Heile (2014) reported that less than one half of patients for whom insulin was recommended used insulin and Polonsky, et al (Polonsky, Fisher, Guzman, et al, 2005) noted that 28.2% of patients with type 2 diabetes were unwilling to use insulin.   

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 life style 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 anti-hyperglycemics. 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.

Conclusion

Glycemic control, prevention of diabetic complications, and slowing the progression of the disease requires the use of insulin in type 1 diabetics and a combination of oral anti-hyperglycemics and eventually, insulin for most patients who have type 2 diabetes. Key learning points for the safe use of the anti-hyperglycemics are:

Each anti-hyperglycemic medication has a specific mechanism of action. These can be summarized as follows:

  • 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, risk for weight gain, effectiveness in the level of glucose control, and the adverse effects. The oral anti-hyperglycemics should be used with caution in patients who have renal impairment.

Hypoglycemia is relatively common with insulin and the sulfonylureas. Repaglinide may cause symptomatic hypoglycemia and pramlintide may cause post-prandial hypoglycemia. The other anti-hyperglycemics do not cause hypoglycemia when used as monotherapy but may cause hypoglycemia if they are used in combination with another anti-hyperglycemic.

The choice of which drug to use (aside from insulin for patients who have type 1 diabetes) will depend on many factors, eg. age, com-morbidities.

There are levels of blood glucose and HbA1c that are considered optimal. But the goals of therapy and the anti-hyperglycemics used to reach those goals must be chosen with consideration of the patient’s age, co-morbidities, the duration of their disease, the benefits and risks of each drug (As they apply to the patient), and the likelihood that they can attain treatment goals.  

Type 1 diabetics must use insulin. The current recommendations are to use insulin analogs and either MDI or a continuous infusion pump 

Pramlintide is the only other injectable approved for the treatment of type 1 diabetes.  Oral anti-hyperglycemics are not approved for the treatment of type 1 diabetes. 

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. These can be first-line drugs if metformin is contraindicated.

α-glucosidase inhibitors, bromocriptine, colesevelam, and pramlintide are considered to be third-line drugs,

There are no unequivocal guidelines regarding what 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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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), Registered Nurse (RN)

Topics:

Advance Practice Nurse Pharmacology Credit, CPD: Practice Effectively, Diabetes, Medical Surgical, Pharmacology


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