Strategies for insulin therapy in type 2 diabetes.

Abstract: Chronic hyperglycemia in type 2 diabetes is responsible for an array of microvascular and macrovascular complications that can lead to significant morbidity and mortality. Several well-conducted large clinical studies have shown that normalizing blood glucose levels can help prevent the onset and slow the progression of complications from diabetes. As many as 25% of patients treated with oral hypoglycemic agents require the addition of insulin therapy to compensate for the progression of [beta]-cell failure and an inability to maintain glycemic control. Various strategies incorporating the use of insulin early in the course of the disease have been developed to meet this goal, and include the use of basal-bolus insulin regimens as well as bedtime insulin injections. The pharmacokinetic properties of the new insulin analogs (eg, insulin lispro, insulin aspart, insulin glargine) offer significant advantages, such as improved control of nocturnal hypoglycemia with basal insulin glargine, and improved postprandial glucose control, with insulin lispro or insulin aspart.

Key Words: combination therapy, diabetes, insulin

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Type 2 diabetes, the second most common disease necessitating patient-physician contact in the United States, (1) is a group of related disorders with distinct pathogenic mechanisms. Hyperglycemia, the common denominator, is associated with comorbidity that includes obesity, hypertension, and peripheral vascular disease. The natural history of diabetes is often complicated by various microvascular and macrovascular sequelae that can lead to blindness, end-stage renal disease, lower-extremity amputation, and atherosclerosis resulting in heart attack or stroke. (2,3)

Much has been learned about the pathogenesis of this frequently encountered and difficult-to-manage metabolic disorder. The basic pathogenic factors in type 2 diabetes have been identified as impaired insulin secretion, decreased glucose uptake by muscles and other tissues (insulin insensitivity), and increased hepatic glucose production. (4)

Diabetes mellitus affects approximately 18 million people in the United States, roughly 6% of the overall population, with more than 1 million new cases diagnosed annually. (5) Diabetes may actually be more endemic than these figures indicate; potentially one undiagnosed individual exists for every one identified. (6) By far, the largest number of individuals with diabetes--approximately 90% of the overall total diabetes population--has type 2 diabetes. (2)

Approaches to Management

Traditional approach

The traditional approach to the management of type 2 diabetes includes dietary modification and exercise. (7) When these modalities prove inadequate in controlling the patient's hyperglycemia, pharmacologic intervention is indicated, in the form of oral hypoglycemic agents, insulin, or both. (8) Five classes of oral hypoglycemic agents are currently available: the sulfonylureas, the nonsulfonylurea insulin secretagogues, the biguanides, the [alpha]-glucosidase inhibitors, and the thiazolidinediones. Each class of drugs has a distinct mechanism of action (Table 1), (9) and the drugs may be used as monotherapy or in combination with other oral hypoglycemic agents or insulin. An extensive review of the various oral hypoglycemic therapies useful in the treatment of type 2 diabetes indicates that most of these agents lower glycated hemoglobin (A1C) concentrations by approximately 1 to 2% (Table 1). (9)

Among insulin therapies, options include rapid-acting, intermediate-acting, and long-acting human insulin preparations (regular, neutral protamine Hagedorn [NPH], lente [Lente; Eli Lilly and Co, Indianapolis, IN] and ultralente [Ultralente; Eli Lilly and Co] insulins, respectively), (2) and the new insulin analogs (Table 2). (10)

Monitoring and therapeutic goals

The management of diabetes requires vigilant attention to blood glucose levels and alteration of the therapy or dosage as needed. Blood glucose levels can be monitored directly, or indirectly by measuring the A1C fraction. A1C results from a nonenzymatic interaction between glucose and the hemoglobin A molecule. Unlike direct measurements of blood glucose, which assess glycemic control at the moment of testing, measurement of A1C is an indication of the extent of the patient's glycemic control over the preceding 8 to 12 weeks. (2)

The goal of treatment in patients with type 2 diabetes is euglycemia. The individualized treatment should lower blood glucose levels sufficiently to prevent microvascular and macrovascular complications associated with chronic hyperglycemia while also limiting hypoglycemic episodes and excessive weight gain. The American Diabetes Association recommends that A1C concentrations should be lowered to less than 7%, fasting plasma glucose levels should be maintained at 90 to 130 mg/dL (5.0 to 7.2 mmol/L), and 2-hour postprandial plasma glucose concentrations should be less than 180 mg/dL (<10 mmol/L). (8) The American College of Endocrinology recommends even lower glycemic control targets: A1C concentrations of 6.5%, fasting plasma glucose levels of less than 110 mg/dL (<6.1 mmol/L), and postprandial plasma glucose levels of less than 140 mg/dL (<7.8 mmol/L). (11)

Intensive therapy

As a result of the natural progression of type 2 diabetes and loss of [beta]-cell function, traditional treatment regimens incorporating oral agents often fail to help patients achieve these goals over the long term, exposing them to nocturnal hypoglycemia and fasting and postprandial hyperglycemia. Many different regimens of intensive insulin treatment have been developed and studied for their ability to provide better 24-hour glycemic control and to decrease the frequency and severity of long-term complications. (6)

The Diabetes Control and Complications Trial was the first to show that maintaining blood glucose levels as near to normal as possible by way of intensive insulin therapy in patients with type 1 diabetes reduced the risk of microvascular complications. (12) With a cohort of approximately 1,400 patients, one half of whom were free of retinopathy at baseline and the other half of whom had mild retinopathy, the study showed that intensive therapy in the retinopathy-free patients resulted in a reduction of the adjusted mean risk for development of retinopathy of 76%, compared with conventional therapy, and slowed progression among the patients with mild retinopathy by 54%. (12) Further, in comparison with conventional therapy, intensive therapy reduced the occurrence of clinical neuropathy by 60%, albuminuria by 54%, and microalbuminuria by 39%. (12)

Evidence that such improvements could also be achieved in patients with type 2 diabetes subsequently emerged. (13) In 1998, a report of the United Kingdom Prospective Diabetes Study (UKPDS) showed that intensive control of blood glucose levels with an oral sulfonylurea (chlorpropamide, glibenclamide, or glipizide) or insulin significantly decreased the risk of microvascular complications in patients with type 2 diabetes. (14) When compared with a control group treated by conventional means (diet alone), patients in the intensive-treatment group had a 12% lower risk of diabetes-related end points (P = 0.029) and, although not significant, had a 10% lower risk for diabetes-associated death and a 6% lower risk of all-cause mortality. The investigators concluded that most of the risk reduction in any diabetes-related aggregate end point was due to a 25% risk reduction in diabetes-associated microvascular end points (P = 0.0099). No significant difference in microvascular risk reduction was observed among the chlorpropamide, glibenclamide, and glipizide treatment modalities. The UKPDS also showed a trend toward a reduction in diabetes-associated macrovascular complications with intensive treatment compared with conventional treatment, although the difference was not statistically significant.

The Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction Study Group demonstrated that an insulin-glucose infusion followed by intensive subcutaneous insulin injection in diabetic patients who had endured an acute myocardial infarction significantly improved their long-term survival. (15) This effect was sustained over 3.5 years, resulting in an absolute reduction in mortality rate of 11% among patients in the intensive-therapy group.

Berger et al (16) hypothesized that on the basis of pathophysiologic and clinical possibilities, the earlier insulin treatment is begun in the natural history of type 2 diabetes, the greater the amount of available endogenous insulin reserves. To this end, they tested various management strategies involving preprandial insulin injections in a multicenter study of 550 patients with type 2 diabetes. (16) At the end of the 2-year observation period, mean A1C concentrations had declined from 9.6% to 8.1%, with virtually no change in mean body mass index. The incidence of severe hypoglycemia was relatively low, at 0.04 cases per patient per year. (16) Intensive insulin therapy also reduces certain macrovascular risk factors, such as lipoprotein abnormalities and fibrinolytic profiles associated with atherothrombotic risk. (17-19)

Thus, it has been firmly established that intensive therapy, including the early use of insulin in patients with type 2 diabetes, can significantly alter the course of long-term microvascular and, to some extent, macrovascular complications, decreasing morbidity and, in some circumstances, mortality.

New Insulin Analogs

Before the introduction of insulin analogs, insulin therapy was limited in its ability to mimic normal physiologic insulin secretion. Traditional intermediate- and long-acting insulins (NPH insulin, lente insulin, and ultralente insulin) are limited by inconsistent absorption and peaks of action that may result in hypoglycemia (Table 2 and Fig. 1). (10) The pharmacokinetic profiles of the new insulin analogs are distinct from those of the regular insulins, and their onsets and durations of action range from rapid to prolonged (Table 2). (10) Currently, two rapid-acting insulin analogs, insulin lispro and insulin aspart, and one long-acting insulin analog, insulin glargine, are available (Fig. 1).

Insulin lispro

Insulin lispro was compared with human regular insulin in a 6-month, randomized, open-label, crossover trial involving 722 patients with type 2 diabetes. (20) The patients were treated with either insulin lispro immediately before meals or human regular insulin 30 to 45 minutes before meals. Over the study course of 24 weeks, the increase in postprandial serum glucose levels was significantly lower in the insulin lispro group than in the human regular insulin group. At the conclusion of the study, the increase in serum glucose levels at 1 and 2 hours postprandially was 30% and 53% lower, respectively, for the patients receiving insulin lispro compared with the patients receiving human regular insulin. The rates of nocturnal and overall hypoglycemia and the number of asymptomatic hypoglycemic episodes were also lower during treatment with insulin lispro than with human regular insulin. However, A1C concentrations decreased significantly (P < 0.001) and equally with each of the two treatments.

[FIGURE 1 OMITTED]

Insulin aspart

A comparison of insulin aspart with regular insulin in a double-blinded, randomized study of 90 men with type 1 diabetes showed that insulin aspart was superior to regular insulin in controlling 24-hour plasma glucose levels (21); 22% fewer instances of hypoglycemia, defined as plasma glucose levels of 72 to 126 mg/dL (4 to 7 mmol/L), occurred with insulin aspart (P < 0.01). Home blood glucose monitoring confirmed that insulin aspart significantly improved plasma glucose control after lunch and dinner (P < 0.05). Insulin aspart also provided better control of hypoglycemic events than did regular insulin (22 versus 44 events, P < 0.002). Regular insulin proved to be superior for controlling nighttime hyperglycemia, although the investigators noted that the doses of NPH, administered as bedtime basal insulin, may not have been adjusted properly.

Insulin glargine

The long-acting insulin analog insulin glargine was studied in comparison with NPH insulin in 518 patients with type 2 diabetes in an open-label, 28-week, multicenter study. (22) All patients had been treated previously with NPH insulin with or without regular insulin for postprandial serum glucose control. In this study, patients were randomly assigned to receive either insulin glargine or NPH insulin, and the doses were adjusted to attain a target fasting glucose level of less than 121 mg/dL (<6.7 mmol/L). At the conclusion of the trial, the median daily dose of insulin was 0.75 IU/kg in both groups. The two forms of insulin produced similar improvements in A1C concentrations and similar reductions in fasting glucose levels; however, the incidence of nocturnal hypoglycemia was significantly lower among patients treated with insulin glargine than among patients treated with NPH insulin (P = 0.0136) (Fig. 2). (22) This difference represented a 25% reduction in occurrences of nocturnal hypoglycemia between the hours of 12 AM and 6 AM.

Clinical experience with once-daily insulin glargine has led to the opinion that its therapeutic effects may not last for a full 24 hours in all patients. Rather than the flat action profile typically seen in most patients, a slight early peak followed by a waning effect toward the end of the dosing interval is experienced by some patients. This effect may be more evident in patients with type 1 diabetes. Theoretically, twice-daily administration may be an alternative, yet results from a recent study conducted by Burge and Schroeder (23) do not confirm this hypothesis. Comparing an equal dose of insulin glargine administered once-daily versus twice-daily in seven patients with type 1 diabetes, insulin concentrations were equivalent after 24 hours regardless of dosing frequency.

[FIGURE 2 OMITTED]

When insulin glargine became available, the recommended dosing interval was once daily at bedtime. More recently, however, insulin glargine has been approved for use at any time of the day as long as it is administered at the same time each day. (24) Insulin glargine should not be mixed with any other insulin products, as such mixing could alter its pharmacokinetic and pharmacodynamic profiles and make them unpredictable. (25)

Defining a Treatment Strategy

To achieve optimal glycemic control, insulin delivery should mimic a pattern that simulates the normal pattern of insulin production. Despite the fact that oral therapy is easier for patients to initiate than self-administration of one or more daily subcutaneous injections, oral therapy is not always successful. The UKPDS showed that approximately 25% of patients randomly assigned to receive oral agents had to be switched to insulin treatment within 6 years because of lack of efficacy of the oral agents in maintaining good glycemic control. (26)

The progressive deterioration of [beta]-cell function that characterizes the natural history of type 2 diabetes suggests that earlier initiation of insulin therapy may protect [beta] cells from the increasing functional impairment caused by extended exposure to hyperglycemia. (16,27) A study with early insulin treatment conducted in 13 mildly overweight, newly diagnosed type 2 diabetes patients who had failed to respond to diet and exercise alone showed promising results. (28) The patients were given 2 weeks of continuous subcutaneous insulin infusion (CSII) immediately after the cessation, of which they were instructed to maintain glycemic control on diet alone. These patients achieved endogenous insulin levels similar to those during CSII treatment. At 6 months after termination of CSII, 85% of the subjects still maintained good glycemic control. Other investigators also have concluded that using an aggressive insulin regimen to restore glycemic control in the early stages of type 2 diabetes, thus reducing glucose toxicity, may have long-lasting benefits, including the restoration of [beta]-cell function and possible reduction in the rate of [beta]-cell deterioration. (27)

Several special circumstances should be considered when prescribing insulin and insulin analogs; these include gastroparesis, renal failure, pregnancy, and advanced age. In patients with gastroparesis, food stays in the stomach much longer than usual, and blood glucose levels rise only after the nutrients leave the stomach and enter the small intestine. If a patient has severe gastroparesis, the use of a fast-acting insulin analog may lead to immediate postprandial hypoglycemia and eventual hyperglycemia, as the insulin analog will begin to lower blood glucose levels before the nutrients are absorbed in the small intestine. Most patients who have gastroparesis still have some degree of gastric function and can control their symptoms of abdominal bloating and gas by spreading out their consumption of food over time, not overeating, and adjusting the types of food they eat. In a few patients with severe gastroparesis, the use of the older human regular insulin may be more effective at matching the absorption of nutrients to insulin action. There is usually no need to make adjustments in the doses of intermediate- or long-acting insulin.

The kidney is partly responsible for the clearance of insulin, and, like the liver, contributes to glucose production, but to a smaller degree. Renal failure leads to prolonged insulin action and altered pharmacokinetics. The clinician should watch for delayed hypoglycemia due to the delayed peaking of insulin action. For this reason, we prefer the use of the fast-acting insulin analogs with meals as they have the shortest course of action. Normally, if the basal insulin requirements are known and the patient's meal plan is consistent in terms of times and amounts, the dose does not need to be altered.

The primary issue regarding diabetes during pregnancy is that aggressive postprandial glucose control to less than 130 to 140 mg/dL has become the gold standard for women throughout gestation. The rate of perinatal morbidity and mortality is essentially the same as that in the nondiabetic population when proper glucose control is maintained. Although not specifically approved for this purpose by the Food and Drug Administration, fast-acting insulin analogs are routinely used in this patient population along with intermediate-acting insulins, such as NPH insulin. Insulin glargine is relatively new to the US market and is only now being considered in pregnant women, although it has not yet been approved by the Food and Drug Administration for use in this population.

As with all medical conditions, diabetes should be managed with caution in the elderly. It is important to maintain good glycemic control to avoid the acute complications of diabetes such as poor wound healing, cognitive dysfunction, and electrolyte imbalance. It is also very important to avoid hypoglycemia, which could lead to injuries such as falls and broken hips. There must be a balance between adequate glucose control and an avoidance of hypoglycemia. The saying "start low and go slow" works well with the elderly.

Combination Therapy

Regular, long-acting, and NPH insulin, as well as insulin analogs, have been combined with various oral agents to control glycemia and successfully lower fasting plasma glucose levels and A1C concentrations. (29-31) In the UKPDS, (17) the addition of insulin to sulfonylurea therapy resulted in significantly lower A1C concentrations than did insulin alone (P = 0.0066) and a greater number of patients achieving A1C concentrations of less than 7% (47% versus 35%, P = 0.011). Median insulin doses used in combination insulin-plus-sulfonylurea therapy at 6 years were also significantly lower than those used in insulin monotherapy: 0.24 IU/kg (range, 0.16 to 0.40) versus 0.30 IU/kg (range, 0.24 to 0.40) (P = 0.0088). (32)

In a 24-week study in patients poorly controlled on sulfonylurea therapy, the combination of insulin and a sulfonylurea, compared with insulin alone, produced comparable declines in A1C concentrations (2.2 [+ or -] 1.0% and 2.1 [+ or -] 1.0%, respectively) but faster declines in fasting plasma glucose levels (P < 0.0001 at 2 and 4 weeks). (31) Furthermore, improvement in fasting hyperglycemia in the combination group was achieved with an insulin dose approximately 40% lower than that required in patients treated with insulin alone.

Insulin in combination with metformin was shown to be significantly more effective than insulin alone in reducing A1C concentrations (-2.5% versus -1.7%, P < 0.01), with a lower daily insulin dose (mean change from baseline, -4.5 IU/d versus +22.8 IU/d; P = 0.002). (33) In one study, insulin in combination with acarbose has also been shown to cause a statistically significant decrease in A1C concentrations (-0.58% versus +0.11%, P = 0.0001) and postprandial hyperglycemia (P = 0.0001) compared with insulin and placebo after 26 weeks of treatment. (34,35) Thiazolidinediones added to established insulin therapy have significantly reduced A1C concentrations ([greater than or equal to]1%) and daily insulin dose requirements compared with insulin alone. (29,30,36)

In a 24-week trial, patients who had been inadequately controlled on one or two oral hypoglycemic agents were found to attain target A1C concentrations of 7% or less when bedtime insulin glargine or NPH insulin was added to their regimen. (37) Insulin doses were systematically and aggressively titrated by using a simple algorithm to achieve a fasting plasma glucose level of 100 mg/dL or less (Table 3). This resulted in patients reaching A1C targets in both the insulin glargine group (58.0%) and the NPH insulin group (57.3%). However, complete treatment success, rigorously defined as reaching target A1C levels without a documented episode of hypoglycemia, was achieved by more subjects receiving insulin glargine than subjects receiving NPH insulin (33.2 versus 26.7%, P < 0.05). Insulin doses increased in a similar manner in both groups, although at study end the mean daily doses of insulin glargine were higher (total dose, 47.2 [+ or -] 1.3 IU; dose adjusted for body weight, 0.48 [+ or -] 0.01 IU/kg) than were the daily doses of NPH insulin (total dose, 41.8 [+ or -] 1.3 IU; dose adjusted for body weight, 0.42 [+ or -] 0.01 IU/kg). Despite the higher doses of insulin glargine, rates of hypoglycemia, expressed as events per patient-year, were significantly lower with the insulin analog than with NPH insulin (symptomatic events, 13.9 versus 17.7, P < 0.02), as were confirmed events of episodes of plasma glucose levels of 72 mg/dL or less ([less than or equal to]4 mmol/L) (9.2 versus 12.9, P < 0.05) and 56 mg/dL or less ([less than or equal to]3.1 mmol/L) (3.0 versus 5.1 episodes, P < 0.003). The hypoglycemia data from this study demonstrate that insulin glargine is better suited for use as a once-daily basal insulin regimen than is NPH insulin.

Bedtime NPH insulin

The use of NPH insulin at bedtime has been studied as a means of strictly controlling fasting plasma glucose levels. A study among 12 obese men with type 2 diabetes whose fasting plasma glucose levels were poorly controlled, even with maximal doses of sulfonylureas, showed that good glycemic control could be achieved with insulin. (38) After a 4-week sulfonylurea washout period, during which the study subjects were treated by diet alone, the subjects received NPH insulin at bedtime for 16 weeks, beginning at a dose of 0.15 IU/kg, which was titrated upward until a fasting glucose level of 80 to 115 mg/dL (4.4 to 6.4 mmol/L) was achieved. Within 6 weeks, mean fasting plasma glucose levels had been reduced from 263 [+ or -] 16 mg/dL (14.6 [+ or -] 0.9 mmol/L) to 106 [+ or -] 11 mg/dL (5.9 [+ or -] 0.6 mmol/L); the mean bedtime dose of NPH insulin was 80 [+ or -] 9 IU/d (0.86 [+ or -] 0.10 IU/kg). The target level for normalization was maintained until the end of the study, 72.0 [+ or -] 0.5 mg/dL (4.00 [+ or -] 0.03 mmol/L) at week 16. A1C concentrations declined over the course of the 16 weeks, from 10.90 [+ or -] 0.05% to 7.2 [+ or -] 0.2%, confirming good glycemic control. Episodes of mild or moderate hypoglycemia occurred at a rate of 3.4 [+ or -] 1.0 per patient, and there were no instances of severe hypoglycemia. This regimen also resulted in improved insulin secretion and insulin sensitivity.

Premixed insulin

In patients with type 2 diabetes, twice-daily regimens of insulin mixtures provide similar glycemic control as an intense regimen of multiple daily injections. (39) Split self-mixed insulin regimens are effective for helping patients achieve glycemic control, yet an inherent risk of error exists. By combining the insulins themselves, patients can encounter problems with mixing technique and inaccurate dosing ratios, potentially reducing the effectiveness of the short-acting insulin. The benefits of premixed insulin formulations, such as a human insulin 70/30 mixed suspension (70% NPH insulin and 30% regular insulin), include reduced errors and improved dosing accuracy as well as the convenience of using a single vial. (40,41)

Premixed rapid-acting insulin analogs

Rapid-acting insulin analogs are also available as manufactured premixed insulin formulations in combination with intermediate-acting insulin. Various fixed-ratio mixtures of insulin preparations exist, including mixtures of insulin lispro, which contains 75% protamine-based intermediate-acting neutral protamine lispro (NPL) and 25% rapid-acting insulin lispro, and insulin aspart, which contains 70% insulin aspart protamine suspension and 30% insulin aspart. The pharmacokinetic and pharmacodynamic profiles of NPL have been shown to be comparable with those of NPH insulin. (42) In a study comparing the pharmacodynamic parameters of 70/30 human insulin with those of 70/30 insulin aspart protamine/insulin aspart, the insulin aspart formulation demonstrated faster onset and greater peak of action. (43)

Premixed 75/25 NPL/insulin lispro was studied in comparison with premixed 70/30 human insulin in 89 patients with type 2 diabetes in a 6-month, randomized, open-label, two-period crossover study. (44) During a 2- to 4-week lead-in period, patients were treated with 70/30 human insulin. After this, they received either (1) twice-daily therapy with 75/25 NPL/insulin lispro for 3 months, after which they were crossed over to receive 70/30 human insulin using the same dosing frequency for an additional 3 months, or (2) the alternate treatment sequence. Mean insulin doses were similar between treatments. Blood glucose levels after the morning meal were significantly lower during treatment with 75/25 NPL/insulin lispro than with 70/30 human insulin (8.95 [+ or -] 2.17 versus 10.00 [+ or -] 2.28 mmol/L [161 [+ or -] 39 versus 180 [+ or -] 41 mg/dL], respectively, P = 0.017). Treatment with 75/25 NPL/insulin lispro produced similar significant blood glucose results 2 hours after the evening meal as well (75/25 NPL/insulin lispro, 9.28 [+ or -] 2.15 [167 [+ or -] 39 mg/dL] versus 70/30 human insulin, 10.27 [+ or -] 2.76 mmol/L [185 [+ or -] 50 mg/dL], P = 0.014). Blood glucose levels at other time points, A1C concentrations, daytime hypoglycemia, or nocturnal hypoglycemia did not differ significantly between treatment groups.

In another study, the premixed 70/30 aspart mixture was compared with premixed 70/30 human insulin administered twice a day in a randomized 12-week, open-label trial in 294 patients with type 1 or type 2 diabetes. (45) There was no significant difference in A1C concentration between groups, although mean blood glucose levels after treatment with the aspart mixture were significantly lower (by approximately 1.0 mmol/L, P < 0.05) after breakfast, before lunch, after dinner, and at bedtime, compared with blood glucose levels after treatment with the human insulin mixture at each time point. The incidence of hypoglycemia did not differ between groups, and weight gain was not significant during the study period with either insulin mixture.

Basal-bolus insulin

The basal-bolus insulin strategy, which can be used in patients with either type 1 or type 2 diabetes, incorporates the concept of providing continuous basal insulin secretion throughout the day and night with brief increases in insulin levels at the time of meal ingestion through the administration of bolus doses.

The use of preprandial regular insulin with bedtime NPH insulin as the basal insulin (Fig. 3A) has been a common strategy for intensive insulin therapy in the United States. However, since regular insulin should be administered 20 to 40 minutes before a meal, a risk of hypoglycemia exists if the meal is delayed. If regular insulin is given just before a meal, high postprandial glucose levels and delayed hypoglycemia may result. A strategy that provides flexibility in the mealtime administration of insulin is the use of the rapid-acting insulin analogs insulin lispro and insulin aspart, administered immediately before meals, and a long-acting insulin, such as ultralente insulin, as the basal insulin (Fig. 3B). However, these regimens are associated with unpredictable nocturnal hypoglycemia and day-to-day instability of blood glucose patterns because of intrapatient variability of the effect of ultralente insulin and its peak action profile. (46) NPH insulin, which exhibits peak action 5 to 7 hours after administration, has also been used in combination with rapid-acting insulin analogs, commonly given twice daily, but the disadvantages of NPH insulin used in this manner are similar to those of ultralente insulin. (47) Because of its time to peak action, NPH insulin should be given every 6 hours, or 4 times per day, to be effective as a basal insulin. (48)

[FIGURE 3 OMITTED]

Improved mealtime glucose control with the rapid-acting insulin analogs has exposed the gaps in basal insulin coverage provided by the traditional intermediate- and long-acting insulin preparations. Administration of a once-daily basal insulin analog, such as insulin glargine, which has a relatively smooth pharmacokinetic profile, may result in a more physiologic pattern of basal insulin replacement. Insulin glargine in combination with a rapid-acting insulin (Fig. 3C) has demonstrated effective glycemic control and is associated with a lower incidence of nocturnal hypoglycemia (49) than are other insulin preparations currently used for basal insulin supplementation. (49-53)

In a 4-week trial, 256 patients with type 1 diabetes who had already been receiving a basal-bolus multiple daily insulin regimen were given blinded treatment with insulin glargine once daily (at bedtime) or unblinded treatment with NPH insulin once daily (at bedtime) or twice daily (at bedtime and before breakfast). (52) Injections of regular insulin were administered before meals, according to the patient's usual regimen. Basal insulin doses were titrated to maintain fasting blood glucose levels between 72 and 126 mg/dL (4 and 7 mmol/L) during the first 3 weeks of the study. The study required that the initial insulin glargine dose be calculated from the total of the two doses of NPH insulin for patients who were receiving NPH insulin twice daily before the study; this resulted in a downward titration of the insulin glargine doses. Thus, at study end point, after the completion of titration, median basal doses of insulin glargine were similar to the prestudy doses in patients receiving NPH insulin once daily. Blood glucose measurements were obtained by patient self-monitoring. At the conclusion of the study, insulin glargine demonstrated better efficacy than NPH insulin in lowering fasting plasma glucose levels, with adjusted mean levels of 166 mg/dL (9.2 mmol/L) and 203 mg/dL (11.3 mmol/L) for insulin glargine and NPH insulin, respectively (P = 0.0001). This clinically meaningful effect was seen as early as 1 week.

The availability of mealtime and basal insulin analogs, combination therapy with oral agents, and the use of insulin regimens comprising basal and mealtime (bolus) insulin components that better simulate normal insulin secretion represent important advances in insulin therapy. All of these approaches can have a significant impact on treatment outcomes.

As described in this review, insulin analogs offer several therapeutic benefits, yet one potential drawback is the expense of these newer agents. The analogs typically cost twice as much as older insulin products, such as human regular insulin and NPH insulin. Some patients and providers may view this as a deterrent, particularly if these drugs are not covered by insurance plans. However, for patients with type 1 diabetes who require an insulin pump, the cost of using insulin analogs may be less costly. In a study by Garg et al, (54) multiple daily injections of insulin glargine and insulin lispro or insulin aspart in a basal-bolus regimen were shown to be less costly than an external insulin pump. As with all drug therapies, the potential benefits of the analogs will need to be weighed against cost when determining individualized drug regimens.

Conclusion

The effective management of diabetes can significantly alter the course of long-term microvascular and, to some extent, macrovascular complications, thus reducing both morbidity and mortality. Clinical experience with intensive therapy for type 2 diabetes offers convincing evidence of the benefits of early insulin use in a regimen providing strict 24-hour control of blood glucose levels. New insulin analogs offer significant advantages in terms of pharmacokinetics, resulting in improved postprandial glycemic control (with insulin lispro and insulin aspart) and enhanced control of nocturnal hypoglycemia (with insulin glargine).

Table 1. Efficacy of oral hypoglycemic drugs (a)

                                                              A1C
                                                         reduction (a)
Class                           Mechanism of action           (%)

Sulfonylureas                   Insulin secretagogues       0.9-2.5
Meglitinides                    Nonsulfonylurea insulin     0.6-1.9
                                secretagogues
Biguanides                      Insulin sensitizers         0.8-3.0
Thiazolidinediones              Insulin sensitizers         1.1-1.6
[alpha]-Glucosidase inhibitors  Inhibition of               0.4-1.3
                                carbohydrate absorption

(a) A1C, glycated hemoglobin.
Adapted with permission from Inzucchi. (9)

Table 2. Characteristics of insulin and insulin analog
formulations (a,b)

Insulin            Onset of            Peak          Duration of
formulation     action (h) (b)      action (h)       action (h)

Lispro             5-15 min            1-2               4-5
Regular           30-60 min            2-4               6-8
NPH (a)            1-2                 5-7              13-18
Lente              1-3                 4-8              13-20
Ultralente         2-4                 8-10             18-30
Glargine           2                   Flat             24-30

(a) NPH, neutral protamine Hagedorn.
(b) Onset of action expressed as hours unless otherwise indicated.
Adapted with permission from Burge and Schade. (10)

Table 3. Weekly titration schedule (a)

                                                             Insulin
2-Day mean FPG                                               increase
(mg/dL)                        (mmol/L)                      (IU/d)

100-120                        5.6-6.7                         2
120-140                        6.7-7.8                         4
140-180                        7.8-10.0                        6
[greater than or equal to]180  [greater than or equal to]10    8

(a) FPG, fasting plasma glucose.
Treat to a target FPG of [less than or equal to]100 mg/dL (5.6 mmol/L).
Start with 10 IU/d bedtime basal insulin and adjust weekly based on FPG
self-monitoring. Do not increase dosage if plasma glucose was
[less than or equal to]72 mg/dL at any time during the preceding week.
Small insulin decreases (2 to 4 IU/d) are permitted if severe
hypoglycemia or plasma glucose was <56 mg/dL during the preceding week.

Accepted September 21, 2004.

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RELATED ARTICLE: Key Points

* Clinical studies reveal that normalizing blood glucose and mimicking normal insulin secretion in patients with type 2 diabetes may prevent the onset and delay the progression of diabetic complications.

* Traditional regimens have failed to maintain glycemic control because of the progressive decline of [beta]-cell function, resulting in patients requiring insulin therapy.

* Strategies have been developed to provide exogenous insulin.

Steven V. Edelman, MD, and Candis M. Morello, PHARMD, CDE 

From the Division of Diabetes and Metabolism, San Diego Veterans Affairs Medical Center, and University of California, San Diego, School of Pharmacy and Pharmaceutical Sciences, San Diego, CA.

Reprint requests to Steven V. Edelman, MD, Division of Diabetes and Metabolism, San Diego Veterans Affairs Medical Center, 3350 La Jolla Village Drive (111G), San Diego, CA 92161. Email: [e-mail]