Below you will find a short article on Diabetes. One of your classmates noticed an error in this article: a sentence in the article reads “a person with type 2 diabetes does not respond to insulin therapy” – you will see I have highlighted this line in the article. Some time ago it was thought that type 2 diabetes was not treatable with insulin, and I would like to blame outdated information for the author’s mistake but this article is taken from a 2011 publication! Perhaps they were just grossly oversimplifying when distinguishing between type 1 and type 2 diabetes. Anyway, the point is, it is not uncommon to see a type 2 diabetic on insulin therapy, particularly as the disease progresses. For the sake of clarification, I have attached a journal article about insulin therapy for type 2 diabetes. To access it, double click on the red ‘thumbtack’ icon next to the highlighted text. You will not be tested on this information for this class...so you can save it to read in your spare time ;)
~ Stacy
Ch mistry I I
KETONE BODIES AND DIABETES
Blood glucose is elevated within 30 minutes following a meal containing carbohydrates. The elevated level of glucose stimulates the secretion of the hormone insulin from the pancreas, which increases the flow of glucose into muscle and adipose tissue for the synthesis of glycogen. As blood glucose levels drop, the secretion of insulin decreases. When blood glucose is low, another hormone, glucagon, is secreted by the pancreas, which stimulates the break­ down of glycogen in the liver to yield glucose.
In diabetes mellitus, glucose cannot be utilized or stored as glycogen because insulin is not secreted or does not function properly. In type 1, insulin-dependent diabetes, which often occurs in child­ hood, the pancreas produces inadequate levels of insulin. This type of diabetes can result from damage to the pancreas by viral infections or from genetic mutations. In type 2, insulin-resistant diabetes, which usually occurs in adults, insulin is produced, but insulin receptors are not responsive. Thus a person with type 2 diabetes does not respond to insulin therapy. Gestational diabetes can occur during pregnancy, but
Diabetes can be treated with injections of insulin.
k to e Ith blood glucose levels usually return to normal after the baby is born. Mothers with diabetes tend to gain weight and have large babies.
In all types of diabetes, insufficient amounts of glucose are avail­ able in the muscle, liver, and adipose tissue. As a result, liver cells synthesize glucose from noncarbohydrate sources (gluconeogenesis) and break down fat, elevating the acetyl CoA level. Excess acetyl CoA undergoes ketogenesis, and ketone bodies accumulate in the blood. As the level of acetone increases, its odor can be detected on the breath of a person with uncontrolled diabetes who is in ketosis.
In uncontrolled diabetes, the concentration of blood glucose exceeds the ability of the kidney to reabsorb glucose, and glucose appears in the urine. High levels of glucose increase the osmotic pressure in the blood, which leads to an increase in urine output. Symptoms of diabetes include frequent urination and excessive thirst. Treatment for diabetes includes a change to a diet limiting carbohy­ drate intake and may require medication such as a daily injection of insulin or pills taken by mouth.
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R. Keith Campbell; John R. White Jr.
Posted: 03/20/2003; J Am Pharm Assoc. 2002;42(4) © 2002 American Pharmacists Association
Abstract and Introduction
Abstract
Objective: To review the increasingly common use of insulin therapy in patients with type 2 diabetes and the practical aspects of initiating insulin therapy in these patients. Data Sources: Recent scientific and clinical literature identified through MEDLINE searches for the years 1995-2001 using the terms oral agents, type 2 diabetes, insulin therapy, glycemic control and diabetic complications, glucose toxicity, insulin lispro, insulin aspart, and insulin glargine. Study Selection: Reports of key large (1,000 patients or more) and significant smaller, randomized, controlled clinical trials were reviewed. For studies comparing insulin analogs, the authors reviewed a sampling of the identified trials for their characteristics and clinical importance. Data Synthesis: Tight blood glucose control can help reduce the risk of diabetes complications. Evidence suggests that early insulin therapy can help correct the underlying pathogenetic abnormalities in type 2 diabetes and improve long-term glycemic control. For these reasons, some diabetes experts advocate the initiation of insulin therapy earlier in the course of type 2 diabetes than has been common in the past. Insulin regimens should be designed to mimic the body's natural physiologic secretion of insulin, including the basal amounts released continuously by the pancreas and the insulin surges produced in response to glucose loads. Using new insulin analogs is a useful approach to achieving this ideal. Insulin glargine provides a nearly constant, peakless release of insulin when injected subcutaneously once daily. Two new rapid-acting insulin analogs, insulin lispro (Humalog -- Lilly) and insulin aspart (NovoLog -- Novo Nordisk), enhance patients' flexibility in terms of meals by permitting injection immediately before meals, rather than 30 minutes before meals, as with regular insulin. Conclusion: Patients should be reassured that early initiation of insulin therapy is a positive event that should improve their long-term health and does not represent a decline in the course of their disease.
Introduction
Type 2 diabetes mellitus is the most common form of the disease, affecting up to 95% of patients -- an estimated 15 million Americans.[1] While pancreatic b cells fail to secrete insulin in patients with type 1 diabetes, those with type 2 are believed to have one or both of two underlying pathophysiologic defects: insulin resistance and/or abnormal insulin secretion.
Insulin resistance involves a failure of patients' peripheral tissues to respond to and use insulin -- and therefore glucose -- as efficiently as they should. In addition, the insulin fails to properly signal the liver to decrease its glucose production (hepatic insulin resistance), leading to unopposed hepatic production of glucose. Both defects produce elevated plasma glucose concentrations.
As type 2 diabetes worsens, impaired insulin secretion becomes evident. First, early-phase insulin secretion -- the rapid release of stored insulin in response to meals -- is lost. Later in the course of the disease, late-phase insulin secretion, involving newly manufactured insulin, becomes impaired as well.[1]
Although some controversy still exists as to whether impaired insulin secretion or insulin resistance is the primary defect in type 2 diabetes, the prevailing view is that insulin resistance precedes the onset of diabetes by many years.[2]
Pancreatic b cells compensate for insulin resistance by continually increasing insulin secretion to keep blood glucose levels in the normal range. Eventually, the b cells are unable to keep up with increasing insulin resistance, and hyperglycemia occurs. Chronic hyperglycemia may also cause so-called "glucose toxicity," a term coined in 1990 to describe impaired insulin secretion secondary to prolonged hyperglycemia.[3,4] Hyperglycemia appears to inhibit the increase in insulin secretion normally seen in response to an elevation in blood glucose.[3] The exact mechanisms for this b cell dysfunction are not fully understood; they may include a direct effect of hyperglycemia on the processes involved in the b cells' glucose metabolism or insulin secretion or the "overworking" of the b cells in such a way as to deplete them of a substance essential to their capacity to secrete insulin.[3,4] In addition, hyperglycemia appears to worsen insulin resistance.[5,6]
Since individuals with type 2 diabetes do not require injected insulin to survive, many people consider it the mildest form of diabetes. In fact, type 2 diabetes is a very serious disease with devastating medical complications. Like type 1 diabetes, type 2 diabetes can cause microvascular complications (diabetic retinopathy, nephropathy, and neuropathy). People with type 2 diabetes are also at greater risk for macrovascular complications (atherosclerosis, coronary artery disease, stroke, and peripheral vascular disease).
To make matters worse, the development of type 2 diabetes is insidious and often goes undetected for years. Study results suggest that the onset of type 2 diabetes occurs as many as 10 to 12 years before the clinical diagnosis of the disease and that the microvascular complications may begin to develop during this interim period.[7,8] In fact, diabetes may first be diagnosed when one of its complications becomes manifest, for example, when retinopathy is detected during a routine eye examination.[1] Further, the United Kingdom Prospective Diabetes Study (UKPDS) showed that type 2 diabetes is a progressive disease that worsens regardless of the treatment given.[9] Because of the progressive nature of the disease, health care professionals must frequently assess the patient's treatment regimen and make adjustments in the medications selected to achieve target blood glucose and glycosylated hemoglobin (A1c) concentrations.
In this article, the general approach to clinical management of type 2 diabetes is reviewed, and the emerging role of insulin therapy -- including the use of newer insulin analogs -- for this condition is presented.
Goals for and Types of Treatment
Appropriate initial treatment for a patient with type 2 diabetes depends primarily on his or her fasting plasma glucose (FPG) level. According to an algorithm we developed (see Figure 1), if FPG is less than 200 mg/dL, therapy should begin with lifestyle modifications: meal planning aimed at reducing caloric and carbohydrate intake and regular aerobic exercise.[10]
Figure 1. Algorithm for Drug Therapy in Patients With Type 2 Diabetes.
The targets for blood glucose control, as recommended by the American Diabetes Association, are fasting preprandial blood glucose levels between 80 mg/dL and 120 mg/dL, bedtime glucose levels between 100 mg/dL and 140 mg/dL, and A1c levels of less than 7%. If the patient's FPG is 200 mg/dL or greater, or if diet and exercise alone fail to adequately control blood glucose levels, the patient is usually started on oral agents. In 1995 the only oral hypoglycemic agents available in the United States were sulfonylureas, which lower blood glucose levels primarily by stimulating the pancreas to secrete more insulin. Since then, a number of different classes of oral agents have become available, including the following:
· The a-glucosidase inhibitors, acarbose (Precose -- Bayer) and miglitol (Glyset -- Pharmacia), which slow the absorption of carbohydrate from the small intestine.
· A biguanide, metformin, which acts against insulin resistance (especially in the liver) and reduces hepatic glucose output.
· The thiazolidinediones, pioglitazone (Actos -- Takeda; Lilly) and rosiglitazone (Avandia -- GlaxoSmithKline), which act primarily on peripheral tissues to decrease insulin resistance and increase insulin sensitivity.
· The meglitinides (or "short-acting insulinotropic agents"), repaglinide (Prandin -- Novo Nordisk) and nateglinide (Starlix -- Novartis), which are rapid-acting stimulators of insulin secretion.
If monotherapy fails to achieve treatment objectives after 3 months, a second type of oral agent may be added, exploiting these agents' different mechanisms of action.[10] The most frequently used combinations include a sulfonylurea plus metformin, a sulfonylurea plus acarbose or miglitol, repaglinide or nateglinide plus metformin, a sulfonylurea plus a thiazolidinedione, and a thiazolidinedione plus metformin.
According to our algorithm, if the patient's initial FPG is between 250 mg/dL and 300 mg/dL, one should assume that some degree of glucose toxicity is present and treat the patient with insulin in combination with an oral hypoglycemic agent. Some common insulin/oral combinations include a sulfonylurea in the morning plus neutral protamine Hagedorn (NPH, or isophane) insulin (intermediate-acting) or insulin glargine (Lantus -- Aventis; long-acting) at bedtime; insulin lispro (Humalog -- Lilly) before meals plus a sulfonylurea in the morning; acarbose or miglitol plus isophane insulin or insulin glargine; metformin plus isophane insulin or insulin glargine; and a thiazolidinedione plus isophane insulin or insulin glargine. Isophane insulin is usually given at bedtime to suppress hepatic glucose production and lower fasting blood glucose levels. Various types of insulins and insulin analogs are discussed later in this article.
If the initial FPG levels are more than 400 mg/dL, or if combination therapy fails, a switch to insulin therapy alone is warranted.[10]
Rationale for Tight Glycemic Control
The evidence that tight blood glucose control can reduce the risk of diabetic complications is now overwhelming. The Diabetes Control and Complications Trial (DCCT)[11] compared the effects of intensive insulin therapy with conventional insulin regimens in 1,441 patients with type 1 diabetes over an average treatment period of 6.5 years. Intensive insulin therapy consisted of three or more daily insulin injections guided by frequent blood glucose monitoring, along with monthly visits to the study center and more frequent contact by telephone to review and adjust dosage regimens. In contrast, conventional insulin therapy consisted of one or two daily insulin injections with less frequent glucose monitoring and examinations once every 3 months. Glycemic control was better in the intensively treated group; the average A1c level for those patients was 7%, compared with 9% for those in the conventionally treated group. The effect of this improvement was striking: Intensive insulin therapy reduced the risk of developing retinopathy by 76%, neuropathy by 60%, and nephropathy by 54%.[11]
One of the major unanswered questions raised by the DCCT was whether the results were applicable to patients with type 2 diabetes. Most researchers suspected they were, but proof was lacking until the results of the Kumamoto Study[12] were published in 1995. The Kumamoto Study was similar to the DCCT except that it involved 110 nonobese subjects with type 2 diabetes. Like the DCCT, it compared intensive insulin therapy with conventional treatment and showed benefits similar to those seen in the DCCT. It demonstrated that tight blood glucose control is as beneficial in type 2 diabetes as it is in type 1 diabetes. However, some researchers questioned whether the findings from this study, which was carried out in lean and insulin-sensitive patients in Japan, could readily be applied to typically obese and insulin-resistant patients with type 2 diabetes in the United States.
Another large interventional study, the UKPDS,[9,13,14] helped settle this question. The UKPDS involved 5,102 people with type 2 diabetes and was conducted from 1977 to 1997 in 23 medical centers throughout the United Kingdom. A part of the study, UKPDS33,[13] used 3,867 volunteers, more than one-third of whom were overweight. Patients were randomly assigned to groups receiving either conventional dietary treatment or intensive blood glucose control using either insulin or a sulfonylurea. The insulin-treated patients were started on once-daily injections of extended insulin zinc suspension (Ultralente), with short-acting insulin added as necessary. The oral agent regimens used were chlorpropamide 100-500 mg, glibenclamide 2.5-20 mg, and glipizide 2.5-40 mg. The goal for the intensively treated group was FPG less than 6 mmol/L (108 mg/dL) and, in insulin-treated patients, premeal glucose of 4-7 mmol/L (72-126 mg/dL). The intensively treated group showed a 25% reduction in the risk of microvascular complications, especially advanced diabetic retinopathy, and a 16% reduction in the risk of heart attacks. Since many of the volunteers in this part of the study were overweight, the results were thought to be more applicable to Americans with type 2 diabetes than those of the Kumamoto Study.[12,13]
In UKPDS34,[14] overweight subjects with type 2 diabetes (more than 120% of ideal body weight) were divided into three groups. One group (411 subjects) was given conventional dietary therapy. Another group (151 subjects) received intensive blood glucose control with chlorpropamide, glibenclamide, or insulin, similar to those in the intensively treated group in UKPDS33.[13] A third group received intensive treatment with metformin. As in other arms of the UKPDS,[9] the goal for the intensively treated group was FPG less than 6 mmol/L (108 mg/dL). Compared with the group receiving conventional treatment, patients receiving metformin had lower A1c levels, a 32% decrease in the risk of diabetic complications, a 42% decrease in the risk of diabetes-related deaths, and a 36% reduction in the risk of death from all causes. Further, patients taking metformin experienced less weight gain and fewer episodes of hypoglycemia than those taking a sulfonylurea or insulin, and metformin was shown to be more effective than sulfonylureas or insulin in preventing diabetic complications, deaths from all causes, and strokes.[14]
Another study involved patients who already had advanced complications. In the Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study,[15] patients presenting with myocardial infarction and hyperglycemia (blood glucose concentrations greater than 200 mg/dL) were randomly assigned to receive either conventional treatment "according to standard practice" (including diet therapy, oral agents, and/or insulin) or intensive insulin therapy (insulin drip in the intensive care unit followed by multiple daily injections). In the 3-year follow-up period, the group receiving intensive insulin therapy had an 11% decrease in absolute mortality and a 28% decrease in the relative risk of mortality.[15]
A growing body of evidence focuses on the prognostic importance of postprandial hyperglycemia.[16] Further, findings from a number of studies suggest that postprandial hyperglycemia is an important risk factor for death from cardiovascular disease.[17-19] Recently, the Funagata Diabetes Study[20] proved that impaired fasting glucose tolerance (as demonstrated by postprandial hyperglycemia) more than doubles the risk of death from cardiovascular disease, whereas impaired fasting glucose has no effect.
Role of Insulin Therapy
Mounting evidence suggests that insulin therapy can help correct the underlying pathogenetic mechanisms responsible for type 2 diabetes, namely, insulin resistance and impaired insulin secretion. Based on research in animal models and patients with diabetes, many researchers believe that glucose toxicity from hyperglycemia contributes to both the insulin resistance and b cell impairment seen in type 2 diabetes.[21,22] (Note that varying degrees of glucose toxicity always occur when blood glucose is elevated.) In animal models, chronic hyperglycemia has been shown to reduce b cell mass through induction of apoptosis.[23] In vitro studies using human b cells show that even mild, short-term hyperglycemia blunts the glucose-stimulated insulin response.[21,24,25] Research has also shown that hyperglycemia increases insulin resistance and that improving glycemic control improves insulin sensitivity.[26,27] Hyperglycemia is thought to worsen insulin resistance by down-regulating the glucose transport system.[5]
In a number of studies, insulin therapy greatly improved insulin secretion in patients with type 2 diabetes, presumably by reducing hyperglycemia.[22,28] Some studies have also demonstrated an improvement in peripheral insulin sensitivity after insulin therapy in type 2 diabetes.[6,29-31] Even short-term insulin therapy appears to result in long-term improvement in blood glucose control, especially when administered in the earliest stages of diabetes.[5,28] Based on these observations, some diabetes experts have advocated initiating intensive insulin therapy early in the course of type 2 diabetes, or immediately after a diet and exercise regimen fails, in an effort to preserve remaining b cell function and improve long-term glycemic control.[5,21] Exceptions to this recommendation may be necessary for developmentally disabled patients or those with Alzheimer's disease.
Skyler[5] has also advocated short-term insulin use in patients with type 2 diabetes during periods of metabolic decompensation -- as in the case of acute illness, stress, or hospitalization -- to reregulate glucose levels. He has suggested that insulin can also be added to oral agents during such periods and continued for a period ranging from a few days to a few weeks. Pregnancy is also a widely accepted indication for temporarily switching to insulin therapy.[1]
Components of Intensive Insulin Therapy
The basic goal of tight control of blood glucose using intensive insulin therapy is to mimic insulin secretion by the normal pancreas. This involves designing a regimen that includes a long-acting or intermediate-acting insulin preparation that approximates basal insulin secretion (i.e., the small amount of insulin the pancreas secretes continuously) and a short-acting insulin preparation that is administered before mealtimes and mimics the extra insulin the pancreas secretes to handle the postprandial rise in blood glucose levels (see Table 1 ). While the nondiabetic pancreas constantly alters the amount of insulin secretion in response to changes in blood glucose concentrations, people using intensive insulin regimens to treat diabetes must frequently monitor their blood glucose levels and adjust insulin doses accordingly.
Table 1. Table 1. Activity Profiles of Various Insulin Preparations
Preparation
Onset
Peak
Duration
Rapid-acting
5 minutes
7-12 hours
1-24 hours
In addition to insulin products containing individual types of insulin, commercially available combination products -- such as 70/30 and 50/50 mixtures of isophane and regular insulin -- provide some patients appropriate doses that can be taken with a single injection ( Table 1 ).
The design of an insulin regimen for an individual patient depends on a number of factors, including the degree of impairment in insulin secretion, the degree of insulin resistance, and the patient's willingness to intensify insulin therapy. Early in the diabetes disease process, when the pancreatic b cells still retain most of their function, a single injection of intermediate-acting insulin before breakfast or at bedtime, or a long-acting insulin product given at bedtime, may achieve normoglycemia.[1] This could be instituted either as monotherapy or in combination with other agents, such as sulfonylureas or thiazolidinediones; many combinations are possible.
More often, however, two injections are needed to meet treatment target levels. Most commonly, a two-injection regimen involves a mixture of intermediate-acting and short-acting insulins injected before breakfast and before dinner. This can be effective in patients with type 2 diabetes who still secrete substantial amounts of insulin.
Patients who have lost virtually all their capacity to secrete insulin may be candidates for a daily multiple-injection regimen (three or more injections per day) similar to that for a patient with type 1 diabetes. In this regimen, the patient injects long-acting insulin at bedtime and takes rapid- or short-acting insulin before each meal. This regimen not only affords excellent blood glucose control but also gives the patient greater flexibility with regard to eating and exercise patterns.[1]
Advent of Insulin Analogs
In recent years, insulin analogs that mimic normal insulin secretion better than traditional insulins have become available. Human insulin works well when secreted directly into the bloodstream by the pancreas. When it is injected into subcutaneous tissue, however, human insulin is absorbed slowly, and often unpredictably, into the bloodstream. An insulin analog is an insulin molecule modified to give it a more desirable activity profile.
The first insulin analog approved for use was insulin lispro, which became commercially available in August 1996. In insulin lispro, the positions of lysine residue B29 and proline residue B28 of the human insulin molecule have been transposed. Since proline residue B28 is believed to be crucial to the formation of stabilizing dimers, this transposition allows the molecules to dissociate from each other more readily and the insulin to be absorbed into the bloodstream more quickly (see Figures 2A and 2B).[32]
Whereas regular insulin has an onset of action of about 30 minutes,[1] a peak action of 2 hours to 5 hours, and a duration of action of between 5 hours and 8 hours, insulin lispro begins working in less than 15 minutes, peaks in 30 minutes to 60 minutes, and has a duration of action of about 3 hours. In practical terms, this means that insulin lispro can be injected immediately before or even after a meal (as opposed to regular insulin, which must be injected 30 minutes before a meal). Further, its rapid peaking follows more closely the peak in blood glucose after a meal. Thus, compared with regular insulin, insulin lispro peaks more rapidly (when it is needed) and disappears more quickly (when it is not needed). Insulin lispro has been shown to reduce postprandial hyperglycemia in both type 1 and type 2 diabetes. In a large multinational study[33,34] of patients with type 2 diabetes, insulin lispro before meals reduced postprandial hyperglycemia, with less hypoglycemia later, than did regular insulin.
Insulin aspart (NovoLogÊNovo Nordisk), another short-acting insulin analog with an action profile similar to that of insulin lispro, received Food and Drug Administration (FDA) approval in 2001. Its proline residue at position B28 is replaced by aspartic acid. The negative charge of the aspartic acid decreases the molecule's self-association, as occurs with insulin lispro.[32]
To date, only a handful of studies have examined the effects of insulin aspart on glycemic control.[35] Various studies carried out in patients with type 1 diabetes have shown that substituting insulin aspart for regular human insulin in various insulin regimens can result in smaller postprandial glycemic excursions, lower A1c levels, and fewer episodes of severe hypoglycemia (see Table 2 ).[36-38]
A long-acting insulin analog, insulin glargine (Lantus -- Aventis), was approved for marketing by FDA in April 2000 and became available in U.S. pharmacies in May 2001. In the insulin glargine molecule, the C terminal of the B chain has been lengthened by two arginine residues, and the asparagine residue at A21 has been replaced with glycine (see Figure 2C). This results in a shift in the molecule's isoelectric point to a slightly acidic pH, which renders it completely soluble at pH 4 (the pH of the injection solution) but much less soluble at the higher physiologic pH. Thus, when injected, insulin glargine forms a subcutaneous microprecipitate and dissolves in a slow, consistent manner, with no pronounced peak, and is absorbed into the bloodstream gradually over a 24-hour period. This manner of insulin delivery approximates normal basal insulin secretion more closely than do isophane insulin, insulin zinc (Lente), or insulin zinc extended suspensions, which have pronounced peaks and shorter durations of action (see Figure 3).[32]
Recent clinical studies suggest that using insulin glargine as the basal insulin results in better glycemic control with less risk of hypoglycemia ( Table 2 ).[39,40] To date, the only difference noted in safety profile between insulin glargine and isophane insulin is that a much greater proportion of patients on insulin glargine report mild pain at the injection site; this is possibly related to its acidity.[41]
It is too early to know exactly what role insulin glargine will eventually play in treating type 1 and type 2 diabetes. Based on current evidence, insulin glargine appears to be at least as safe and effective as isophane insulin and may supplant its use in some regimens. Its ideal use would be as a basal insulin, with insulin lispro administered before meals.
A new insulin formulation, Humalog Mix 75/25, contains neutral protamine lispro (NPL) and lispro in a ratio of 75:25. The rationale behind this product is that mixtures of short-acting and intermediate-acting insulins have proven extremely useful and convenient, but insulin lispro is known to react with isophane insulin over prolonged periods of time. In NPL insulin, insulin lispro has been cocrystallized with protamine, producing an intermediate-acting insulin with an activity profile similar to that of isophane insulin. A recent study comparing Humalog Mix 75/25 with human insulin 70/30 (isophane:regular) found that the new formulation resulted in improved postprandial glycemic control and comparable overall glycemic control.[42]
Continuous subcutaneous insulin infusion using insulin pumps can also closely mimic physiologic insulin secretion. Insulin pumps are programmed to infuse insulin at a basal secretion rate, and patients can deliver extra boluses of insulin to cover meals and snacks. Traditionally, regular insulin was used, but insulin lispro has now replaced it in the majority of patients. Insulin aspart is approved for use in insulin pumps. The rationale for using insulin lispro or aspart in pumps is that, compared with regular insulin, the insulin lispro or aspart bolus works more quickly at mealtime, and adjusting the basal infusion rate translates more rapidly into circulating insulin.[42,43]
A double-blind crossover study compared the use of regular human insulin with that of insulin lispro in pumps. The investigators randomly assigned 30 patients with type 1 diabetes to receive regular insulin or insulin lispro for 3 months before crossing over to the other insulin preparation for 3 months. At the end of the treatment period, the average A1C levels were significantly lower in the insulin lispro group than in the human insulin group (7.66 ± 0.13 versus 8.00 ± 0.16%). The incidence of hyperglycemia, which was 8.4 ± 1.3 episodes per 30 days before randomization, decreased to 6.0 ± 0.9 for the insulin lispro group and 7.6 ± 1.3 for the regular insulin group in the final month of the study.[43]
Overcoming Patient-Related Obstacles to Use
Starting insulin therapy can be an unsettling change for patients, and they may be resistant to adhering to treatment and monitoring regimens for a number of reasons. Pharmacists can help smooth the transition by listening to and addressing patients' fears.
For example, patients may believe that the switch to insulin represents a decline in the course of their diabetes. In the past, people with long-term, poorly controlled diabetes and advanced complications were often put on insulin in a last-ditch effort to achieve glycemic control, but patients may not know about the changing ideas about how insulin should be used in the course of diabetes therapy.[44] Patients today need to be reassured that insulin use is a positive step that should improve blood glucose control, possibly restore some b cell function, and maximize prospects for good health in the future.
In addition, many patients have "needlephobia" and are emotionally unprepared to give themselves injections every day. Physicians can help address this problem by minimizing the number of injections used in the regimen without compromising good glycemic control. (This, of course, can only be done in patients who do not need intensive control.)Through proper instruction, pharmacists and diabetes educators can reduce or remove the threat patients perceive when it comes to injections. Once patients have actually injected themselves, most come to realize that injections are not as painful as they had anticipated. In fact, injecting insulin is less painful than lancing fingers for self-monitoring of blood glucose levels.[44] Also, a number of jet injector devices work by delivering a fine stream of insulin under high pressure. Some patients find these devices to be less painful and, therefore, more tolerable than needles.
Another potential fear is hypoglycemia. Fortunately, hypoglycemia does not appear to be a major complication of insulin therapy for patients with type 2 diabetes. In the UKPDS, for example, there was only a modest frequency of hypoglycemic events.[13] Further, patients who are on more finely tuned insulin regimens using insulin lispro and/or insulin glargine may be even less likely to experience serious hypoglycemia.
Patients with diabetes need to be on rigorous dietary and exercise programs, and this need is accentuated when insulin therapy begins, as many patients experience substantial gains in weight in the first few months of treatment. In patients treated with insulin for 6 to 12 months, weight gains of up to 6 kg have occurred.[45] However, weight gain is not inevitable; some patients who take insulin do not gain weight, and others actually lose weight. Moreover, many of the studies that report weight gain have not included efforts to educate patients on how to use diet and exercise to control weight. When treating patients for whom weight gain associated with insulin use would be problematic, dietary and exercise recommendations should be adjusted accordingly.
Conclusion
With the increasing realization of the importance of aggressive blood glucose control, especially early in the course of the disease, more and more patients with type 2 diabetes are potential candidates for intensive insulin therapy. Fortunately, the advent of insulin analogs has created the potential for finely tuned insulin delivery. Pharmacists can help patients recognize that initiating insulin therapy is a step forward in managing their disease and protecting their long-term health.
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Reprint Address
R. Keith Campbell, FAPhA, CDE, College of Pharmacy, Washington State University, PO Box 646510, Pullman, WA 99164-6510. Fax: 509-335-0162. E-mail: rkcamp@wsu.edu .
 
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