Special Feature: Injectable Therapy for Diabetes Mellitus: Insulin and Beyond
Special Feature
Injectable Therapy for Diabetes Mellitus: Insulin and Beyond
By Richard A. Harrigan, MD,
Associate Professor of Emergency Medicine, Temple University School of Medicine, Philadelphia, PA
Introduction
The pharmacologic armamentarium for the treatment of diabetes mellitus (DM) is expanding rapidly. Oral antidiabetic agents, which include five classes of drugs, recently have been reviewed elsewhere.1 Parenteral therapy for DM, which includes a variety of insulins and insulin analogues, as well as two new injectable non-insulin agents, also is growing. The emergency physician must be knowledgeable of the various drugs, their onsets and durations of action, as well as their adverse effect and toxicity profiles. The following is a pharmacology update on parenteral agents for the treatment of DM.
Insulins and Insulin Analogues
Insulin therapy can be characterized as prandial (bolus) insulin, basal insulin, or an insulin supplement to correct hyperglycemia.2,3 The first group functions similarly to the physiologic release of insulin when food is ingested. Basal insulin agents mimic the relatively constant, but low-level release of endogenous insulin that affects lipolysis and glucose release from the liver. Supplemental insulin also can be given in response to blood sugar spikes that arise anywhere along the way in the eating cycle. Regular and NPH insulins target both prandial and basal insulin needs, whereas insulin analogues address these two components separately.2,3
An awareness of the varying onsets of action, peaks, and durations of these agents is vital when assessing hypoglycemic patients in the ED to not underestimate maximum effect and to anticipate what lies ahead after discharge. All these times are difficult to commit to memory, and they are subject to individual patient variation in absorption and distribution (Table). Two recent reviews on the topic—written by the same author— report different durations of action for some of these agents, providing evidence that pharmacokinetic variation exists.2,3 Some basic rules can be deduced, however.
Rapid-acting agents. The newer rapid-acting insulin analogues (e.g., insulin lispro and insulin aspart) have an onset of action within a few minutes and peak about the same time the traditional short-acting agent (regular insulin) begins its onset of action approximately 30-60 minutes. The duration of effect for these rapid-acting agents is shorter than that of regular insulin. Remember when contrasting the rapid-acting insulin analogues (lispro and aspart) with standard regular insulin that these rapid-acting analogues reach twice the maximal concentration in half the time of regular insulin. These differing onsets of action make the timing of insulin injection an issue; rapid-acting agents should be injected at mealtime, whereas regular insulin should be administered 20-30 minutes before the meal.3
Pre-mixed agents. The premixed insulins are no longer simply combinations of regular and NPH (Table). The familiar Humulin 70/30 is 70% NPH and 30% regular insulin; the less commonly used Humulin 50/50 is half NPH and half regular. They combine the onset times of regular insulin with the duration of the NPH. Note that the 75/25 premixed insulin is actually 75% NPL (functionally indistinguishable from NPH) and 25% insulin lispro. Thus, in parallel to traditional premixed regimens, it combines the onset time of the lispro (5-15 min) with the duration of the basal insulin (10-16 hr). To further complicate this situation, there is another analogue combination available that is also a 70/30 mix 70% NPL and 30% aspart. Its onset and duration are the same as that of the 75/25 agent discussed above. One way to remember which agent is which is to look at the trade names. Humulin 70/30 and Humulin 50/50 are the traditional mixes of NPH and regular. Humalog 75/25 and Novolog 70/30 contain insulin analogues; thus, they have a rapid onset of action (Table).
Long-acting agents. Introduced in the United States in 2001, insulin glargine (Lantus) forms a precipitate at the injection site, enabling it to act as a depot preparation and thereby, releasing the drug slowly during the course of the day (and night) without having a peak (Table). Its strength seems to be a lower rate of hypoglycemia than is seen with NPH insulin.2,3 Insulin glargine is given customarily at bedtime, although there are data that show it can be administered successfully at breakfast or dinner also.3
Adverse effects. The principal side effect of insulin and its analogues is hypoglycemia, the timing of which can be anticipated by knowledge of the onset of action, peak effect, and duration of each agent. Beyond Insulin: Other Injectable Agents Traditionally, if a diabetes patient says he takes shots for glucose control, this statement has meant that he was taking insulin. That is no longer true. Two agents were approved by the Federal Drug Administration (FDA) this past spring: one for treatment of type I and II DM and the other solely for use in type II DM.
Pramlintide (Symlin). This drug can be used in either type I or type II diabetes patients in whom adequate blood sugar control cannot be achieved with insulin alone. This is the first agent beyond insulin to be approved for type I DM. This drug is a synthetic version of amylin, a natural hormone secreted by the pancreatic beta cell in response to hyperglycemia in parallel to the release of insulin. Its principal mechanism of action is to inhibit gastric emptying and, to a lesser degree, suppress the secretion of glucagon; it also suppresses the appetite.4 The half-life of pramlintide is about 50 minutes, and it is metabolized primarily by the kidneys. Hepatic dysfunction should not affect this agent, and there is no need for dose reduction in patients with a creatinine clearance of more than 20 mL/min; it has not been studied in dialysis patients.5
Pramlintide is administered immediately prior to major meals; type II diabetes patients begin with 60 µg subcutaneous (sc) and may be increased to 120 µg if no significant nausea has occurred in 3-7 days. The dose should be reduced to 60 µg if the higher dose is associated with significant nausea. Importantly, the pre-prandial rapid-acting or short-acting insulin dose should be reduced by 50% when pramlintide is initiated; this caution includes pre-mixed regimens (e.g.,70/30, 75/25 insulin). Once the optimal dose of pramlintide is reached, the insulin regimen should be titrated to fine-tune glucose control. In type I diabetes patients, the initial dose is 15 µg sc, with upward titration in 15 µg-increments until a maximum of 60 µg; similarly, pre-meal insulin should be halved, and dose titration is guided by nausea.5
Blood glucose levels should be monitored frequently during initiation of pramlintide. Injections should be into the abdomen or thigh (not the arm), and should be rotated. The agent must not be mixed with insulin preparations in the same syringe, and it should be injected at least two inches away from the insulin injection site. Missed doses should not be given later. Principal side effects include hypoglycemia and nausea. The drug is contraindicated in gastroparesis, and it should be noted that pramlintide administration will delay absorption of drugs taken concomitantly by mouth. It should not be utilized when prokinetic drugs (e.g., metoclopramide) are used also. The drug is not approved currently for pediatric patients and is FDA pregnancy category C. Overdose data are limited, but severe nausea, vomiting, and dizziness are expected.5
Exenatide (Byetta). Indicated for type II diabetes only, this drug is an incretin a drug class (prototype: glucagon-like peptide-1) that enhances glucose-dependent secretion of insulin from the beta cell, impedes inappropriately high glucagon secretion, and also delays gastric emptying. Exenatide augments insulin release only in the presence of elevated blood sugar; as the serum glucose level falls toward normal, insulin secretion ebbs. Although it modulates glucagon, it does not interfere with the appropriate glucagon response to hypoglycemia. Exenatide reaches peak concentrations approximately two hours after sc injection. The drug is eliminated principally by the kidney. Hepatic insufficiency is not expected to affect exenatide, however, the drug is not recommended in severe renal insufficiency (i.e., creatinine clearance < 30 mL/min).
Exenatide is indicated as a pharmacologic adjunct for type II diabetes patients not achieving adequate glycemic control with metformin, a sulfonylurea, or both; notably, it has not been studied in patients taking insulin, thiazolidinediones (e.g., pioglitazone), meglitinides (e.g., repaglinide), or alpha-glucosidase inhibitors (e.g., acarbose). Adding this agent to sulfonylurea therapy may require dose reduction of the latter. Initial treatment includes administration of a 5-µg dose sc in the proximal arm, thigh, or abdomen at any time within 60 minutes before the morning and evening meal; it should not be given after the meal, and missed doses should not be made up. The dose may be increased to 10 µg twice daily if clinically indicated. It can indirectly cause hypoglycemia if a sulfonylurea is being used also. As with pramlintide, exenatide’s effect on gastric emptying may affect co-administration of other drugs; agents that depend upon achieving a certain threshold for efficacy (e.g., oral contraceptives, antibiotics) should be taken more than one hour prior to exenatide. Principal adverse effects are hypoglycemia (expected only with sulfonylurea therapy), nausea, and decreased appetite. Exenatide is not for use in children or patients with type I diabetes and is FDA pregnancy category C. Limited experimental overdose data demonstrated profound nausea and vomiting, as well as hypoglycemia.
References
1. Harrigan RA, et al. Oral agents for the treatment of type 2 diabetes mellitus: pharmacology, toxicity, and treatment. Ann Emerg Med 2001; 38:68-78.
2. Hirsch IB. Drug therapy: Insulin analogues. N Engl J Med 2005:352:174-183
3. DeWitt DE, Hirsch IB. Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: scientific review. JAMA 2003;289:2254-2264.
4. Chehade JM, et al. A rational approach to drug therapy of type 2 diabetes mellitus. Drugs 2000; 60:95-113.
5. Symlin (pramlintide) prescribing information. Amylin Pharmaceuticals; 2005. http://www.symlin.com.
6. Byetta (exenatide). Presecribing information. Amylin Pharmaceuticals; 2005. http://www.byetta.com.
By Richard A. Harrigan, MD, Associate Professor of Emergency Medicine, Temple University School of Medicine, Philadelphia, PA Introduction The pharmacologic armamentarium for the treatment of diabetes mellitus (DM) is expanding rapidly. Oral antidiabetic agents, which include five classes of drugs, recently have been reviewed elsewhere.1 Parenteral therapy for DM, which includes a variety of insulins and insulin analogues, as well as two new injectable non-insulin agents, also is growing. The emergency physician must be knowledgeable of the various drugs, their onsets and durations of action, as well as their adverse effect and toxicity profiles. The following is a pharmacology update on parenteral agents for the treatment of DM.Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.