Case #1 : Appropriate Selection and Use of Medications

Brandon J. Sucher , PharmD, CDE, AE-C
Allana J. Sucher , PharmD, BCPS
Peter Clapp , PhD

Educational Objectives

Upon completion of this educational activity, participants should be able to:

• Describe current American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) clinical practice guidelines and consensus statements for the management of T2DM.
• Describe the role of available oral and other non-insulin medications in the management of T2DM and the risk of hypoglycemia associated with their use.
• Apply clinical guidelines to assess appropriate use of medications for T2DM, with consideration to the reduction of risks for hypoglycemia.

Introduction

Of the more than 17 million Americans diagnosed with diabetes mellitus (DM) in the United States, 90% to 95% of these patients have type 2 diabetes mellitus (T2DM).1,2 In order to maintain and improve outcomes, there is a need for tight glycemic control and reduction of blood glucose (BG) levels. However, some situations may arise where BG levels are reduced more than desired, resulting in hypoglycemia. Because pharmacists are often engaged with both prescribers and patients, they play a key role in recommending drug therapy and educating on the appropriate use of complex drug regimens to help ensure that glycemic goals are met and the risks of hypoglycemia are minimized. This activity, reviewing effective and appropriate selection of oral and other noninsulin products for glycemic control, is part of a series focusing on reducing the risk of hypoglycemia.

Pharmacologic Management of Type 2 Diabetes Mellitus

Although metformin is often chosen as initial pharmacotherapy for T2DM, it seldom provides long-term control.3,4 To decrease the risk of complications associated with T2DM, patients' treatment regimens need to progress to dual therapy, to triple therapy, and then to insulin therapy to parallel disease progression. Even though insulin is the most effective medication for achieving glycemic goals, insulin regimens are often delayed or not optimally intensified. Additionally, some patients may not achieve optimal therapeutic benefit from any medication due to poor adherence to treatment regimens.

As therapy is intensified to reach glycemic goals in T2DM, it is unrealistic to expect 100% avoidance of hypoglycemia. Therefore, teaching patients how to recognize, prevent, and treat hypoglycemia is an important component of health care for those with T2DM. During treatment selection, it is also important to consider the risk of hypoglycemia associated with each medication.

Goals of Therapy

In 2009, the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) published an algorithm to help health care providers manage patients with T2DM. This algorithm recommends attaining a glycosylated hemoglobin (A1C) level of 6.5% or less. Additionally, the AACE recommends a fasting blood glucose goal of 110 mg/dL or less and a 2-hour postprandial blood glucose goal of <140 mg/dL.2 However, the balance between tight glycemic control and risk of hypoglycemia needs to be managed on an individual basis. Those who should be managed less aggressively include patients with: T2DM for more than 15 years and advanced macrovascular disease; hypoglycemia unawareness; limited life expectancy; or the presence of serious comorbidities.5

 
Progression of Therapy

For most patients, the AACE/ACE algorithm provides a progression from monotherapy, to dual therapy, to triple therapy, then to insulin therapy. When identifying the role of medications within the algorithm, the AACE/ACE considered the degree of hyperglycemia in a patient, the expected A1C-lowering potential of each medication, and the risk of hypoglycemia associated with each medication. The Table includes medications that should be considered in monotherapy, dual-therapy, and triple-therapy regimens.5 Classifying some of these medications as insulin sensitizers, incretin agents, and insulin secretagogues can simplify understanding of the AACE/ACE algorithm. Insulin sensitizers include biguanides and thiazolidinediones (TZDs), incretin agents include dipetidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists, and insulin secretagogues include glinides and sulfonylureas.

If a patient's baseline A1C level is close to goal (ie, <7.5%), monotherapy is appropriate. Unless contraindications are present, metformin should be considered as the first choice for monotherapy. It is also recommended in dual-therapy and triple-therapy regimens due to its well-established safety and efficacy profile. If metformin is contraindicated or not tolerated, a TZD serves as the second choice for monotherapy and as the foundation for dual-therapy and triple-therapy regimens. If these insulin sensitizers are contraindicated or not tolerated, DPP-4 inhibitors or alpha-glucosidase inhibitors are recommended due to their low risk of hypoglycemia.5 

When monotherapy fails to achieve or maintain glycemic control, another medication should be added. If a patient is adhering to an insulin sensitizer, then adding an incretin agent is preferred over adding an insulin secretagogue due to a lower risk of hypoglycemia. GLP-1 agonists are preferred over DPP-4 inhibitors due to greater efficacy and weight-loss benefits. Although GLP-1 agonists have these advantages, their disadvantages include gastrointestinal adverse effects and availability only as injectable formulations. An advantage of DPP-4 inhibitors includes their availability as an oral formulation, and that they are well tolerated. The combination of metformin with a TZD is considered third choice.5 

Adding an insulin secretagogue is considered the fourth choice for dual therapy. For patients close to A1C level goal (ie, <7.5%), preference should be given to glinides over second-generation sulfonylureas due to their greater efficacy in controlling postprandial hyperglycemia. This is because as a patient approaches their goal A1C level, postprandial hyperglycemia contributes more to the elevated A1C level compared with fasting hyperglycemia. For patients with an A1C level >7.5%, second-generation sulfonyureas are preferred over glinides due to their greater ability to lower the A1C level. Either metformin combined with colesevelam or metformin combined with an alpha-glucosidase inhibitor can be considered as a fifth choice for patients close to A1C goal level (ie, <7.5%).5

When dual therapy fails to achieve or maintain glycemic control, another medication should be added. Again, patient adherence should be assessed before adding a medication. As stated previously, triple-therapy regimens should include metformin, unless it is contraindicated or not tolerated.5

For patients with an A1C close to goal level (ie, <7.5%), a triple-therapy regimen should include an incretin agent. For the reasons stated previously, GLP-1 agonists are preferred over DPP-4 inhibitors. However, if a patient is unable to tolerate a GLP-1 agonist, a DPP-4 inhibitor should be used. In order to decrease the risk of hypoglycemia, the third medication in a triple-therapy regimen is preferred in the following order: TZDs, glinides, and second-generation sulfonylureas. If the patient's A1C level is greater than 7.5%, metformin and an incretin agent are also recommended. Glinides, alpha-glucosidase inhibitors, and colesevelam are not recommended as part of a triple-therapy regimen due to their limited A1C-lowering potential.5

For patients with an A1C level <9.0% and symptoms of thirst, increased urination, or weight loss, insulin therapy should be initiated without delay. After the A1C level is <7.5%, the effects of glucotoxicity and lipotoxicity on beta-cell function are reduced. At that point, other medications for T2DM may be initiated with subsequent insulin dose reduction, and it may be possible to discontinue insulin.5

Educational Disclaimer:

Continuing professional education (CPE) activities sponsored by Pharmacy Times Office of Continuing Professional Education are offered solely for educational purposes and do not constitute any form of professional advice or referral. Discussions concerning drugs, dosages, and procedures may reflect the clinical experience of the author(s) or they may be derived from the professional literature or other sources and may suggest uses that are investigational in nature and not approved labeling or indications. Participants are encouraged to refer to primary references or full prescribing information resources.

The author(s), reviewer(s), and editor(s) have made extensive efforts to ensure that the information, including treatments, drugs, and dosage regimens, is accurate and conforms to the standards accepted at the time of publication. However, health care professionals should always consult additional sources of information and exercise their best professional judgment before making clinical decisions of any kind. In particular, the reader is advised to check the product information provided by the manufacturer of a drug product before prescribing or administering it, especially if the drug is unfamiliar or is used infrequently.

 
References :

1. Centers for Disease Control and Prevention (2009, July 23). Number (in Millions) of Civilian/Noninstitutionalized Persons with Diagnosed Diabetes, United States, 1980-2007. Available at: www.cdc.gov/diabetes/statistics/prev/national/figpersons.htm . Accessed July 20, 2010.
2. Rodbard HW, Blonde L, Braithwaite SS, et al (AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract .2007;13:S1-S68.
3. Boyle PJ, Zrebec J. Management of diabetes-related hypoglycemia. South Med J . 2007;100:183-194.
4. Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet . 2005;365:1333-1346.
5. Rodbard HW, Jellinger PS, Davidson JA, et al (AACE/ACE Glycemic Control Algorithm Consensus Panel). Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology Consensus Panel on type 2 diabetes mellitus: An algorithm for glycemic control. Endocr Pract . 2009;15:541-559. 

Brandon J. Sucher, PharmD, CDE, AE-C, is Associate Professor of Pharmacy Practice, Regis University School of Pharmacy, Denver, Colorado.
Allana J. Sucher, BCPS, is Assistant Professor of Pharmacy Practice, Regis University School of Pharmacy, Denver, Colorado.
Peter Clapp, PhD, is Assistant Professor of Pharmacy Practice, Regis University School of Pharmacy, Denver, Colorado. Brandon J. Sucher, PharmD, CDE, AE-C; Allana J. Sucher, PharmD, BCPS; and Peter Clapp, PhD have no relevant affiliations or financial relationships to disclose. The staff of Pharmacy Times Office of Continuing Professional Education has nothing to disclose relative to this activity.

(Source : pharmacy times)

Case #2 : Focus on Optimal Insulin Use

Brandon J. Sucher , PharmD, CDE, AE-C
Allana J. Sucher , PharmD, BCPS
Peter Clapp , PhD

Educational Objectives :

• Upon completion of this educational activity, participants should be able to:
• Identify the different insulins used in T2DM therapy and their advantages and disadvantages.
• Identify and minimize the risk of hypoglycemia associated with treatment of T2DM.
• Identify the etiology and clinical consequences of hypoglycemia.
• Cite pharmacologic interventions for the management of hypoglycemic episodes.

Type of Activity: Application

Introduction

Of the more than 17 million Americans diagnosed with diabetes mellitus (DM) in the United States, 90% to 95% of these patients have type 2 diabetes mellitus (T2DM).1,2 To maintain and improve outcomes, there is a need for tight glycemic control and reduction of blood glucose (BG) levels. Some situations may arise, however, where BG levels are reduced more than desired, resulting in hypoglycemia. Because pharmacists are often engaged with both prescribers and patients, they play a key role in recommending drug therapy and educating on the appropriate use of more complex therapies, such as insulin, to help ensure that glycemic goals are met and the risks of hypoglycemia are minimized. This activity, reviewing safe and effective use of insulin products, is part of a series focusing on reducing and managing risks from hypoglycemia.

Insulin for the Treatment of T2DM

Insulins have been described as rapid acting, short acting, intermediate acting, long acting, and premixed. This classification can be simplified for patients by describing insulins as mealtime insulins, maintenance insulins, and premixed insulins. Mealtime insulins include insulins used before meals (ie, rapid-acting and short-acting insulins). Maintenance insulins include intermediate-acting and long-acting insulins. Premixed insulins contain a combination of mealtime and maintenance insulin. See the Table for a listing of insulin formulations.3-17

Maintenance Insulins

Maintenance insulins meet the patient's need for an appropriate level of insulin between meals and during sleep. An advantage of insulin neutral protamine Hagedorn (NPH) is its ability to be mixed with mealtime insulins, thus decreasing the required number of injections for patients using both formulations.7,13 Disadvantages of insulin NPH include a peak effect, which results in a higher risk of nocturnal hypoglycemia compared with other maintenance insulins. An advantage of insulin detemir is that it has a less pronounced peak effect than insulin NPH, which may result in a lower risk of nocturnal hypoglycemia. A disadvantage of insulin detemir is its incompatibility with mealtime insulins in the same syringe, resulting in an increased number of required injections for patients using both formulations.12 Patients may administer insulin glargine once daily anytime during the day, as long as they are consistent. If a patient is switched from insulin NPH dosed twice daily to insulin glargine dosed once daily, the initial dose of insulin glargine should be 80% of the total daily dose of NPH. If the patient is switched from insulin NPH dosed once daily to insulin glargine, the initial dose of insulin glargine does not need to be adjusted. Advantages of insulin glargine include lack of a significant peak effect, decreased risk of nocturnal hypoglycemia, and a longer duration of action, allowing for once-daily injections. Disadvantages of insulin glargine include its incompatibility with mealtime insulins in the same syringe and a higher incidence of injection-site pain, due to its acidic pH.11

Mealtime Insulins

Regular human insulin should be administered 30 minutes prior to meals. Advantages of regular human insulin include that it is the least expensive mealtime insulin and it is available in a concentrated formulation. Disadvantages of regular human insulin include a more variable absorption compared with other mealtime insulins, a longer duration of action compared with other mealtime insulins (which may result in postprandial hypoglycemia), and a less convenient dosing regimen with regard to meals.8,14

Advantages of insulin aspart, insulin glulisine, and insulin lispro include a more rapid onset of action, a shorter duration of action, and less intrapatient variability in time course of action compared with regular human insulin. These characteristics allow for a more flexible dosing schedule and a decreased risk of postprandial hypoglycemia compared with regular human insulin.

Premixed Insulins

Premixed insulin includes a combination of a mealtime insulin and a maintenance insulin; therefore, premixed insulins should be administered before meals. They have comparable durations of action, but differ with respect to onset of action based on the mealtime insulin in the premixed insulin. Patients who eat small, frequent meals (more than 3 meals per day) are not likely to achieve glycemic control with premixed insulins.

Management of Hypoglycemia

Teaching patients how to recognize, prevent, and treat hypoglycemia is an important component of health care for patients with T2DM who are using insulin or even just oral therapies. When achieving glycemic control with insulin, it is unrealistic to expect 100% avoidance of hypoglycemia. The incidence and severity of hypoglycemia, as well as associated fears, can be reduced with appropriate goal setting, self-monitoring of BG, and education.18

Hypoglycemia can be mild to severe, and asymptomatic or symptomatic. Hypoglycemia is considered severe when patients are unable to self-treat low BG due to altered consciousness or unconsciousness. If asymptomatic or symptomatic mild-to-moderate hypoglycemia is unrecognized or untreated, it can progress to severe hypoglycemia.

Patients with a long history of T2DM, those experiencing recurrent hypoglycemia, and those with neuropathy may not sense or experience autonomic hypoglycemia symptoms. This phenomenon, called hypoglycemia unawareness, increases the chance of any episode becoming severe before detection. Hypoglycemia unawareness can be alleviated by more frequent self-monitoring of BG or by using a continuous glucose monitoring device.18

Common causes of hypoglycemia include missed meals, increased physical activity, vomiting, diarrhea, alcohol use, emotional or physical stress, and progression of renal or hepatic disease. Patients who are at high risk of hypoglycemia include the elderly and those with hypoglycemia unawareness. Sympatholytic medications (eg, beta-blockers) may mask the symptoms of hypoglycemia mediated by the sympathetic nervous system, but will not block symptoms of the cholinergic nervous system, such as sweating. Caffeine may increase the autonomic symptoms of hypoglycemia, while alcohol may decrease symptoms of hypoglycemia.

Five grams of carbohydrates increase BG by approximately 15 mg/dL.18 Patients should treat the symptoms of hypoglycemia or any BG level <70 mg/dL (regardless of symptoms) with 15 to 20 g of carbohydrates. Examples include 3 to 4 glucose tablets, 8 to 10 hard candies, 4 to 6 oz of fruit juice or soft drinks containing sugar, or 8 oz of milk. If blood glucose is <50 mg/dL, 20 to 30 g of carbohydrates may be needed. If blood glucose is <70 mg/dL 15 minutes after treatment, patients should eat another carbohydrate snack.18 Glucagon emergency kits are available for caregivers to administer to patients who are unable to use oral glucose, those who have altered consciousness, or those who are unconscious.

The patient's family should be educated on how to recognize severe hypoglycemia and the appropriate use of glucagon. Glucagon stimulates both gluconeogenesis and glycogenolysis, but is ineffective if glycogen stores are depleted (ie, after prolonged fasting). Nausea and vomiting may occur in patients treated with glucagon, so patients should be positioned upright to decrease the risk of aspiration. Sustained carbohydrate intake and close observation are necessary, because hypoglycemia may recur after apparent recovery.16

Educational Disclaimer:

Continuing professional education (CPE) activities sponsored by Pharmacy Times Office of Continuing Professional Education are offered solely for educational purposes and do not constitute any form of professional advice or referral. Discussions concerning drugs, dosages, and procedures may reflect the clinical experience of the author(s) or they may be derived from the professional literature or other sources and may suggest uses that are investigational in nature and not approved labeling or indications. Participants are encouraged to refer to primary references or full prescribing information resources.

The author(s), reviewer(s), and editor(s) have made extensive efforts to ensure that the information, including treatments, drugs, and dosage regimens, is accurate and conforms to the standards accepted at the time of publication. However, health care professionals should always consult additional sources of information and exercise their best professional judgment before making clinical decisions of any kind. In particular, the reader is advised to check the product information provided by the manufacturer of a drug product before prescribing or administering it, especially if the drug is unfamiliar or is used infrequently.

References :

• Centers for Disease Control and Prevention (2009, July 23). Number (in Millions) of Civilian/Noninstitutionalized Persons with Diagnosed Diabetes, United States, 1980-2007. www.cdc.gov/diabetes/statistics/prev/national/figpersons.htm. Accessed July 20, 2010.
• Rodbard HW, Blonde L, Braithwaite SS, et al (AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract . 2007;13:S1-S68.
• Apidra [package insert]. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2009.
• Humalog [package insert]. Indianapolis, IN: Eli Lilly and Company; 2009.
• Humalog Mix 50/50 [package insert]. Indianapolis, IN: Eli Lilly and Company; 2009.
• Humalog Mix 75/25 [package insert]. Indianapolis, IN: Eli Lilly and Company; 2009.
• Humulin N [package insert]. Indianapolis, IN: Eli Lilly and Company; 2009.
• Humulin R [package insert]. Indianapolis, IN: Eli Lilly and Company; 2009.
• Humulin 50/50 [package insert]. Indianapolis, IN: Eli Lilly and Company; 2007.
• Humulin 70/30 [package insert]. Indianapolis, IN: Eli Lilly and Company; 2007.
• Lantus [package insert]. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2007.
• Levemir [package insert]. Princeton, NJ: Novo Nordisk Inc; 2009.
• Novolin N [package insert]. Princeton, NJ: Novo Nordisk Inc; 2009.
• Novolin R [package insert]. Princeton, NJ: Novo Nordisk Inc; 2009.
• Novolin 70/30 [package insert]. Princeton, NJ: Novo Nordisk Inc; 2009.
• NovoLog [package insert]. Princeton, NJ: Novo Nordisk Inc; 2009.
• NovoLog Mix 70/30 [package insert]. Princeton, NJ: Novo Nordisk Inc; 2010.
• Boyle PJ, Zrebec J. Management of diabetes-related hypoglycemia. South Med J . 2007;100:183-194.

Brandon J. Sucher, PharmD, CDE, AE-C, is Associate Professor of Pharmacy Practice, Regis University School of Pharmacy, Denver, Colorado.
Allana J. Sucher, BCPS, is Assistant Professor of Pharmacy Practice, Regis University School of Pharmacy, Denver, Colorado.
Peter Clapp, PhD, is Assistant Professor of Pharmacy Practice, Regis University School of Pharmacy, Denver, Colorado.

Brandon J. Sucher, PharmD, CDE, AE-C; Allana J. Sucher, PharmD, BCPS; and Peter Clapp, PhD have no relevant affiliations or financial relationships to disclose. The staff of Pharmacy Times Office of Continuing Professional Education has nothing to disclose relative to this activity.