Why and how to use insulin therapy earlier in the management of type 2 diabetes.

Abstract: Most patients with type 2 diabetes are inadequately controlled on their current therapy. Suboptimal glycemic control can have devastating consequences, such as retinopathy, nephropathy, neuropathy, and cardiovascular disease that may ultimately lead to mortality. Most patients eventually need insulin therapy, and initiating insulin earlier in the course of type 2 diabetes may lead to optimal glycemic control and prevent or delay diabetes-related complications. Although insulin therapy is the most effective method of managing hyperglycemia, it is often delayed owing to concerns about the complexity and inconvenience of treatment regimens; fear of injections, hypoglycemia or weight gain; and the time required to learn how to effectively manage insulin therapy. The development of insulin analogs, biphasic insulin analogs, and more convenient insulin delivery systems may make insulin therapy more manageable and help more patients achieve their treatment goals.

Key Words: type 2 diabetes, insulin, analogs, hypoglycemia

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Despite accumulating evidence regarding the long-term complications of hyperglycemia and more aggressive guidelines for managing type 2 diabetes, more than 60% of patients do not meet their glycemic goals. (1) Poor glycemic control causes considerable morbidity and mortality, increasing the risk for microvascular complications, such as retinopathy, nephropathy, and neuropathy, (2,3) and macrovascular complications, including myocardial infarction, stroke, and peripheral vascular disease. (4)

The current paradigm for the pharmacologic management of type 2 diabetes includes the stepwise introduction of lifestyle modifications followed by the use of oral agents, combinations of oral agents, and then insulin therapy. (5) Although insulin is the safest and most effective therapy when dosed properly, (6) it has often been viewed as "the last resort" for patients with type 2 diabetes. (5) Because there may be long delays before moving to the next step in a conventional stepwise approach, by the time insulin is initiated (or considered), patients often have had the disease for more than 10 to 15 years and have already developed complications. (5)

Moreover, the effectiveness of the stepwise approach in achieving and maintaining target glycemic levels is limited. This was clearly evident in a prospective observational study of more than 7,000 patients, in which the average patient remained at a glycosylated hemoglobin level (A1C) of more than 8% for 5 years, and an A1C greater than 7% for 10 years before insulin therapy was initiated. (7) In addition, a recent study has demonstrated that the percentage of patients with type 2 diabetes achieving A1C <7.0% has decreased in the past decade. (1) These data indicate the clear need for a more aggressive approach to managing type 2 diabetes, which has prompted a growing movement toward initiating insulin earlier in the course of the disease. (5,8,9)

Why Use Insulin Early in the Course of Type 2 Diabetes?

The use of oral antidiabetic drugs (OADs), all of which require some degree of insulin secretion, is often appropriate in the early stages of the disease. However, as insulin secretion continues to diminish with the progressive decline in [beta]-cell function, early insulin replacement can avoid hyperglycemia and help reduce the risk of the microvascular and macrovascular complications associated with poor glycemic control.

Reduced Risk of Microvascular and Macrovascular Complications

The association between hyperglycemia and the microvascular complications of diabetes (eg, retinopathy, neuropathy, and microalbuminuria) and the benefits of adequate glycemic control in reducing the risk of these complications are well established. (2,3,10,11) For example, in the United Kingdom Prospective Diabetes Study (UKPDS), intensive therapy with insulin, a sulfonylurea, or metformin reduced the risk of microvascular disease by 25% (P = 0.0099). (2) In fact, each 1% reduction in A1C was associated with a 37% reduction in microvascular complications (P < 0.0001) and a 21% reduction in any clinical event or death associated with diabetes (P < 0.0001). (4)

There is increasing evidence that intensive glycemic control can also reduce the risk of macrovascular disease and macrovascular events. (2,12-14) In the UKPDS, each 1% decrease in A1C produced a statistically significant reduction in the risk of fatal and nonfatal myocardial infarction (MI) (14%), fatal and nonfatal stroke (12%), heart failure (16%), and amputation or death from peripheral vascular disease. (4) A recent analysis of data from patients with type 1 diabetes from the Diabetes Control and Complications Trial (DCCT), who were observed for an average of 11 years after completion of the study, found that intensive therapy reduced carotid intima-media thickness, as well as the risk of any cardiovascular event, by 42% (P = 0.02) and of nonfatal MI, stroke, or death from cardiovascular disease by 57% (P = 0.02), when compared with conventional therapy. (12)

Results from observational studies confirm that lower glycemic levels are associated with a reduced risk of cardiovascular morbidity and mortality. (13,14) In the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) study, both elevated fasting plasma glucose (FPG) and 2-hour postprandial glucose (PPG) levels were associated with a significantly increased risk of cardiovascular mortality. (13) Results from the Diabetes Intervention Study, a prospective trial of patients with newly diagnosed type 2 diabetes with an 11-year follow-up period, demonstrated a significantly increased risk of MI and mortality with increasing PPG levels. (14)

Improved Cardiovascular Profile

Greater glycemic control with insulin therapy has been shown to improve markers of cardiovascular risk, such as cholesterol, triglycerides, and waist-to-hip ratios. (15-18) Insulin therapy appears to also have a favorable impact on endothelial function, inflammatory markers, and thrombotic factors, benefits that are independent of their associated reductions in diabetes complications. (19-23) For example, insulin therapy has been shown to partially restore insulin-stimulated endothelial function, (19) improve vasodilatation, (20) and improve fibrinolytic profiles. (22)

Reduced Glucotoxicity and Blood Glucose Variability

One major benefit of the early initiation of intensive insulin therapy is a reduction in glucotoxicity. (24,25) Glucotoxicity is defined as a nonphysiologic alteration in cellular function caused by chronic exposure to high glucose concentrations. (26) Glucotoxicity results from [beta]-cell exhaustion and desensitization and may worsen these defects by causing oxidative stress, which can increase the rate of [beta]-cell apoptosis and deterioration in [beta]-cell function. (8,27) However, there is evidence suggesting that these defects can be reversed when blood glucose levels are normalized. In several clinical trials, intensive insulin treatment administered to patients who failed on maximal doses of oral agents significantly improved [beta]-cell function. (25,28,29) In fact, when short periods of intensive insulin therapy are administered early in the disease, it can even result in a temporary "remission," during which dietary intervention alone can be sufficient to provide glycemic control. (8,30,31)

By reducing glucose toxicity and restoring glycemic control, early initiation of insulin therapy can increase peripheral sensitivity to insulin and [beta]-cell function. (25,32,33) In a 2-year trial comparing early insulin therapy to glibenclamide, patients receiving insulin experienced significantly greater reductions in A1C and FPG and higher glucagon-induced C-peptide excretion and plasma insulin levels. (33) Additional studies are needed to confirm these findings.

Glycemic variability may also affect the risk of microvascular disease. Data from the DCCT showed that despite comparable A1C levels, patients receiving conventional therapy (1 or 2 injections daily) experienced a substantial elevation in the risk of retinopathy when compared with patients receiving intensive insulin management ([greater than or equal to]3 daily insulin injections or pump therapy). Hirsch and Brownlee (34) have speculated that this increased risk may be explained by greater variability and more severe glycemic excursions seen with conventional therapy. Recent evidence has further demonstrated that increased oxidative stress markers, which have been implicated in the pathogenesis of diabetic complications, is associated with wide glycemic fluctuations. (35,36)

Reduced Morbidity, Mortality, and Healthcare Costs, and Improved Quality of Life

Greater glycemic control achieved by the early initiation of insulin therapy may reduce morbidity and mortality, limit healthcare costs, and improve quality of life (QOL). Epidemiologic studies, including data from the UKPDS, demonstrate that tight glycemic control is associated with reduced mortality, as reflected by statistically significant 21% and 14% reductions in death related to diabetes and all-cause mortality, respectively, for every 1% reduction in A1C. (4,37,38) Improved glycemic control is also associated with reduced morbidity and hospitalizations owing to diabetes, as well as reduced long-term and short-term economic costs, leading to improved QOL. (4,39-43) In patients with poor glycemic control on OADs, switching to insulin produces statistically significant improvements in treatment satisfaction, general well-being, and QOL. (41,44-47)

What Is "Earlier" Initiation of Insulin?

In most patients with type 2 diabetes, insulin therapy is initiated only when combination therapy with two or three OADs fails and following years of suboptimal glycemic control. Several strategies for earlier initiation of insulin therapy have been proposed, including the short-term use of insulin therapy after diet and exercise programs fail, or as the first therapeutic choice in newly diagnosed patients with severe diabetes symptoms, marked hyperglycemia, or ketonuria. (8,24,34,48,49) Insulin has also significantly improved glycemic control when introduced after a single oral agent fails. (50-52) When starting insulin therapy, continuing oral agents may often provide additional blood glucose control. (52,53)

What Are the Barriers to Initiating Insulin Early?

Despite its significant benefits, insulin therapy is often delayed in clinical practice. Perhaps the most common barriers to insulin therapy are concerns about hypoglycemia and weight gain (see section on "Complications and Adverse Effects of Insulin Therapies"), (49) but, for the majority of patients, the long-term benefits of improved glycemic control with insulin therapy outweigh these risks. (48) Newer insulin options may also minimize the risk of these adverse effects.

Another frequently cited concern about insulin use is the misperception that insulin increases the risk of cardiovascular disease. This misperception may have resulted from epidemiologic studies that reported a correlation between endogenous hyperinsulinemia and coronary heart disease, (54,55) and the Veterans Affairs Cooperative Study of Diabetes Mellitus (VACSDM), which suggested an inverse relationship between coronary events and A1C level in men with type 2 diabetes. (56) Although no prospective randomized trial has shown a beneficial effect of intensive therapy on macrovascular disease in type 2 diabetes, large clinical studies do not support an atherogenic role for insulin therapy, and, if anything, actually demonstrate a reduced cardiovascular risk in subjects with improved glycemic control, including in the setting of acute coronary syndromes. (2,4,12,57,58) In fact, observational studies have reported lower rates of cardiovascular and total mortality among patients on intensive insulin therapy. (59,60)

Because insulin therapy is often viewed as a last resort for patients with type 2 diabetes, insulin use may be delayed and limited to patients with later stages of diabetes who often have irreversible complications of the disease. (5) A recent study by Shah and colleagues (61) reported that diabetes therapy was intensified in less than half of patients with elevated A1C levels, regardless of the specialty of the clinician. In fact, the Diabetes Attitudes, Wishes, and Needs (DAWN) study found that 50 to 55% of nurses and general practitioners delay insulin until it is absolutely necessary. (62) In this study, delaying insulin therapy was significantly less likely when physicians viewed their patients as more adherent to their medication regimen or viewed insulin as more efficacious. In addition, patients, especially those in the United States, often do not believe insulin to be very effective and mostly blame themselves for failing to control their diabetes. (62) Educating patients at the time of diagnosis about the course of type 2 diabetes, the risks of uncontrolled diabetes, and the benefits of insulin therapy can address many of these issues.

Another significant barrier to insulin therapy is the fear of injections. Smaller and finer needles (up to 31G) and more user-friendly delivery devices (eg, disposable insulin pens) enhance the convenience and flexibility of insulin administration, potentially improving treatment adherence and outcomes. (8,63-65) Quick point-of-care demonstrations of insulin administration using these new devices, by either the physician, a nurse, or trained medical technician, will often dispel preconceived notions of pain and discomfort from needle injection. Alternatively, referring patients to a certified diabetes educator to assist in initiating insulin therapy has several advantages. For one, the nurse educator will often have more time available to discuss the rationale and goals of insulin therapy, while at the same time addressing concerns and questions patients may have regarding their diabetes treatment. In addition, nurse educators are often more familiar with tools and techniques to minimize the discomfort and inconvenience of injection. Patients may be more likely to adopt and maintain insulin therapy when given tools to facilitate administration. (66,67)

Patients and physicians may also resist initiating insulin therapy because of concerns about more complicated and time-consuming dosing requirements and a lack of appropriate resources and support, including access to patient education programs and newer and often more expensive technologies and formulations. Reluctance may occur when physicians do not have the time required to teach patients how to inject insulin, monitor their blood glucose, or recognize and treat hypoglycemia. (49,68) In these instances, referral to specialists or diabetes educators may help clinicians provide optimal diabetes care. (61) Clinicians should be aware that newer insulin delivery devices require less time to teach, are easier to use, provide greater flexibility, and are associated with higher levels of satisfaction compared with vials and syringes. (65,66) Unfortunately, in many cases, these devices are more expensive to use and may be limited on certain pharmacy formularies.

Considerations for Insulin Initiation

Glycemic targets need to be individualized for every patient and should take into account a patient's risk of developing microvascular complications. Fasting plasma glucose levels and the magnitude of postprandial excursions are also important factors to consider when determining the most appropriate insulin regimen. Studies have shown that as patients approach target A1C levels, elevations in PPG may play a greater role in glycemic control than elevations in FPG. (35,69) Moreover, a large observational study has shown that inadequate control of PPG may be a greater risk factor for cardiovascular disease and all-cause mortality. (13) Published recommendations for glycemic control provide guidelines for matching daily glycemic control to A1C level. (70-72) For example, the ADA suggests that to achieve and maintain an A1C level <7%, patients should attempt to keep their FPG <130 mg/dL and their PPG <180 mg/dL.

Other important factors to consider when selecting and managing candidates for insulin therapy include a patient's motivation for optimizing glycemic control and the availability of local resources to help patients adhere and adjust to the insulin regimen. (51) Some patients with busy lifestyles may frequently skip meals or be unwilling or unable to adhere to treatment regimens with complicated dosing or titration schedules. For these patients, simplified regimens may be beneficial, at least in the beginning of therapy. In the end, optimal glycemic control and adherence to insulin therapy can be best achieved when therapy is adapted, as much as possible, to a patient's lifestyle, rather than when patients are asked to change their habits to match the action profile of an insulin regimen.

Principles of Insulin Therapy

Ideally, insulin therapy should mimic the endogenous insulin secretion patterns observed in healthy individuals. In the normal state, endogenous insulin levels rise rapidly from a baseline level after a meal, reaching a peak concentration within 15 to 45 minutes and rapidly returning to baseline before the next meal. (64) Therefore, in patients with limited [beta]-cell function, insulin therapy should combine a basal insulin (which provides constant insulin levels throughout the day) with a bolus (prandial) insulin (which produces a rapid increase of insulin immediately after a meal).

All antidiabetic agents can be classified as treatments that address a basal insulin deficiency, a postprandial insulin deficiency, or both. Currently available treatments that primarily address basal coverage include metformin and the thiazolidinediones, neutral protamine Hagedorn (NPH) insulin, and the long-acting insulin analogs, insulin glargine (Lantus) and insulin detemir (Levemir). Treatments that predominantly address postprandial coverage (or bolus treatments) include insulin secretagogues, regular human insulin, exenatide, pramlintide, and the rapid-acting insulin analogs: insulin lispro (Humalog), insulin aspart (Novolog), and insulin glulisine (Apidra). The only products that address both basal and postprandial insulin deficiencies are premixed insulins, such as NPH and regular human insulin premix (Humulin or Novolin 70/30), or the biphasic insulin analog formulations [biphasic insulin lispro (Humalog Mix 75/25) and biphasic insulin aspart (Novolog Mix 70/30)]. Any combination of prandial and basal therapies can be used to address an individual patient's needs.

Basal Insulin Therapies

Basal insulin formulations suppress hepatic glucose production between meals and at night and constitute approximately 40 to 50% of an individual's daily insulin needs. (68) Therefore, in patients with complete [beta]-cell failure, approximately half of the insulin dose should cover the basal insulin requirement.

Traditionally, NPH insulin and Lente and ultralente (two formulations that are no longer available) have been used as basal insulin therapies. However, these treatments have significant limitations, including considerable intra- and inter-patient variability in absorption, and a peaking action profile that does not adequately match physiologic insulin needs. As a result, there is a relatively higher risk of hypoglycemia with the use of these preparations. (68,73,74)

The basal insulin analogs, insulin detemir and insulin glargine, overcome some of the limitations of the conventional basal insulin preparations and offer significant clinical advantages in insulin therapy. These insulin preparations provide relatively reproducible and near-peakless coverage with minimal within-subject variability. (68,75) Clinical trials have demonstrated that basal insulin analogs, when compared with NPH insulin, are associated with similar efficacy and risk of severe hypoglycemia, but lower FPG levels, lower variability in plasma glucose, a more predictable action profile, a reduced risk of nocturnal hypoglycemia, and, in the case of insulin detemir, less weight gain. (76-84) Of note, and particularly relevant in cash-paying patients with limited finances, is that basal or bolus insulin analogs are more expensive than their nonanalog counterparts (NPH and regular insulin).

Bolus Insulin Therapies

Bolus insulin therapies, which include regular human insulin and the rapid-acting insulin analogs, are designed to control postprandial glycemia. Regular human insulin has several disadvantages, including its slow absorption, insufficient and late peak of action, and prolonged duration, which do not adequately match physiologic insulin secretion and result in early postprandial hyperglycemia and an increased risk of hypoglycemia 4 to 5 hours after a meal. Although injecting 30 to 45 minutes before a meal would greatly improve the time action profile of regular insulin and make it more physiologic, most patients fail to inject regular human insulin at the correct time.

The new rapid-acting insulin analogs are effective alternatives that more closely mimic physiologic prandial insulin release due to their more rapid onset and shorter duration of action. As such, these therapies can be administered closer to mealtime and provide improved postprandial glycemic control with fewer episodes of hypoglycemia than regular human insulin. (85-89) Studies evaluating the use of rapid-acting insulin analogs injected immediately after a meal have also shown adequate postprandial glucose control, even when compared with preprandial regular insulin. (90-93)

Mixed Basal/Bolus Therapies

Premixed insulin preparations consist of fixed proportions of basal and bolus components (premixed NPH/regular human insulin 70/30, biphasic insulin lispro 75/25, and biphasic insulin aspart 70/30). These preparations facilitate administration by eliminating the need to manually mix insulins. Each of these formulations aims to provide effective control of both FPG and PPG, while offering the convenience of fewer total daily injections. Premixed insulin analogs, like the rapid-acting insulin analogs, also can be administered closer to mealtime. These formulations provide better postprandial glycemic control with a reduced risk of hypoglycemia compared with premixed human insulin. (9,86,94-96)

Full Basal/Bolus Therapies

Basal/bolus regimens most closely mimic the normal functioning of [beta] cells. They involve the use of a minimally peaking basal insulin analog, such as insulin detemir or insulin glargine, administered in the morning or at bedtime to cover nonprandial needs (overnight and between meals) plus a rapid-acting analog administered at mealtimes. Insulin pump therapy, or continuous subcutaneous insulin infusion, is another option that delivers a rapid-acting insulin analog in controlled doses to meet both basal and prandial insulin needs. (97,98) Centers with expertise in insulin pump therapy report improved glycemic control, lower rates of hypoglycemia, and better quality of life when compared with patients using multiple daily insulin injections. (97,99,100)

Complications and Adverse Effects of Insulin Therapies

Hypoglycemia, weight gain, fluid retention, and, occasionally, allergic reactions have been associated with insulin therapy. Although hypoglycemia is relatively common in tightly controlled patients with type 2 diabetes on insulin therapy or sulfonylureas, the risk of severe hypoglycemia is significantly lower than that observed in type 1 diabetes. (2,10,51) The frequency of these episodes, which are mostly mild or moderate in severity, varies with the type of insulin and the treatment regimen. To reduce the risk of hypoglycemia, patients should be educated about the signs of hypoglycemia and the relationships among physical activity, diet, and insulin administration. (68,101)

Fear of weight gain, a recognized adverse effect of insulin therapy, may also make patients reluctant to use insulin therapy. Weight gains of 5.5 to 16.5 lbs have been observed with insulin treatment during the first year of treatment. (8,33,102) However, the new long-acting insulin analog, insulin detemir, has consistently demonstrated less weight gain than NPH insulin in several clinical trials in type 1 and type 2 diabetes. (78-84) The concomitant use of metformin with insulin therapy may also limit weight gain. (102) In most cases, the benefits afforded by strict glycemic control clearly offset the impact of weight gain. (48)

Initiating Insulin Therapy

To determine the most appropriate therapy for patients with type 2 diabetes with suboptimal glycemic control, clinicians should consider the patient's current treatment status and A1C, FPG, and PPG levels. Self-monitoring of blood glucose (SMBG) can be very useful in determining the appropriate targets for therapy and the most useful treatment regimen for a particular patient. If the patient's elevated glucose levels are primarily due to elevated FPG, a basal therapy may be most appropriate, while a treatment involving basal and bolus components might be more appropriate for patients with greater elevations in PPG.

Patients with Inadequate Control on OADs

The great majority of patients considered for insulin therapy have already used one or more OADs. The clinician must often decide whether to introduce insulin therapy after the second or third OAD when A1C targets have not been achieved. Knowing that each additional OAD achieves an A1C reduction of approximately 1%-1.5%, a decision algorithm has been developed to help advance therapy in type 2 diabetes (see Fig. 1). As discussed earlier, the concept of physiologic insulin replacement for the treatment of hyperglycemia and prevention of diabetes complications needs to be clearly presented and discussed with patients to ensure maximum understanding and acceptance of, and adherence to, insulin therapy.

Once the decision to introduce insulin therapy is made, the clinician must, in collaboration with the patient, determine the regimen that will most likely normalize glycemia while minimizing the adverse effects of therapy, namely hypoglycemia and weight gain. Although the use of basal/bolus insulin therapy or insulin pump therapy is clearly the most physiologic approach to correct both fasting and postprandial hyperglycemia, these intensive regimens are generally reserved for subjects with long-standing type 2 diabetes and advanced [beta]-cell dysfunction. Moreover, because patients with type 2 diabetes can be resistant to insulin use, clinicians typically introduce insulin therapy gradually and intensify treatment based on the patients' therapeutic response. A variety of strategies are now available that have been proven both effective and safe for initiating and advancing insulin therapy in this patient population.

In patients inadequately controlled on OADs, evidence suggests that adding insulin glargine or insulin detemir effectively lowers glycemia with less hypoglycemia, and in the case of detemir, less weight gain, compared with NPH. (76,84) For example, in the Treat-to-Target study, subjects who were not at target A1C while taking one to two OADs received 10 U of NPH insulin or insulin glargine at bedtime. (76) In this 24-week study, investigators used a physician-driven, weekly titration algorithm (Table 1) (76) to adjust the bedtime insulin dose to achieve FPG <100 mg/dL. With average basal insulin doses of 42 to 47 U a day (approximately 0.5 U/kg/d), more than 55% of subjects treated with either insulin achieved the target A1C of <7%. The most marked difference between the two insulin types was a statistically significant reduction in the frequency of nocturnal hypoglycemia in subjects using insulin glargine, and a greater percentage of patients using insulin glargine who achieved target A1C without documented nocturnal hypoglycemia.

[FIGURE 1 OMITTED]

In a similar treat-to-target study of insulin detemir, more than 70% of subjects who received insulin detemir or NPH achieved the target A1C of <7.0%. (84) However, a significantly higher proportion of subjects treated with insulin detemir achieved target A1C without hypoglycemia compared with NPH. Moreover, treatment with insulin detemir was associated with a significantly lower risk of overall and nocturnal hypoglycemia, and significantly less weight gain compared with NPH. In patients inadequately controlled on OADs, insulin detemir should be initiated at a dose of 0.1 to 0.2 U/kg once daily in the evening or 10 U once or twice daily. The dose should be adjusted to achieve glycemic targets.

When adjustment algorithms are simplified, many patients are also able to effectively and safely self-titrate their bedtime basal insulin dose. This was demonstrated in the ATLANTUS study in which patients were given instructions to self-adjust their basal insulin dose by 2 U every 3 days to achieve FPG levels <120 mg/dL. (103) In this study, patients were able to achieve target A1C levels more often using a patient-driven algorithm versus a weekly physician-driven titration.

Studies evaluating basal insulin replacement in insulin-naive patients with type 2 diabetes have important implications. Basal insulin replacement is effective and safe, especially when long-acting insulin analogs are used in place of NPH insulin. In many patients, A1C targets are achieved without reaching FPG targets of < 100 mg/dL. When appropriately implemented, frequent basal insulin dose adjustment algorithms can get patients to target by 3 months of treatment. As with all oral or injectable treatment strategies, the lower the A1C achieved, the greater the likelihood of weight gain and risk of hypoglycemia.

Patients with Inadequate Control on Basal Insulin

For patients managed with basal insulin therapy whose A1C remains elevated despite using high-dose basal insulin, clinicians should consider introducing prandial insulin coverage. Prandial insulin therapy, in the form of rapid-acting insulin, should also be considered when subjects on basal insulin replacement experience nighttime hypoglycemia or unacceptable postprandial hyperglycemia. Overreliance on basal insulin to cover dinner-related hyperglycemia may also be evident when bedtime blood glucose levels are much higher than fasting levels. Options for prandial insulin coverage include regular human insulin preparations or rapid-acting insulin analogs. Today, regular human insulin is used primarily when the higher cost of rapid-acting insulin analogs is a concern.

Because the largest meal of the day in North America is often dinner, starting with one injection of prandial insulin before the evening meal may prove effective for many patients. This "basal-plus" approach can be initiated by giving 10% of the daily basal dose as a rapid-acting insulin preparation before dinner. (34) The basal insulin dose should concomitantly be decreased to reduce the risk of overnight hypoglycemia. This approach, although reasonable, has yet to be tested in randomized controlled trials.

Patients on basal-plus insulin therapy may need to consider additional prandial insulin coverage if A1C goals are not met with two injections per day. Obviously, before changing the insulin schedule, the dinner bolus and nighttime basal doses should be adjusted to achieve target blood glucose levels. An additional dose of prandial insulin, in the form of a rapid-acting insulin analog, can be started as either 3 to 4 U of insulin, or again, 10% of the total daily insulin dose, before one or more of the remaining meals (Table 2). (104-110)

A different option for introducing a rapid-acting component to cover postdinner hyperglycemia, while still maintaining one injection of insulin a day, is the use of a premixed insulin preparation given before dinner. (111,112) Again, the premix insulin analogs aspart 70/30 and lispro 75/25 are preferable to human premix 70/30, given their better physiologic action profiles. This approach was tested in the 1-2-3 study protocol, where subjects with inadequately controlled type 2 diabetes on either oral agents or oral agents plus basal insulin were started on a premixed insulin analog (biphasic insulin aspart 70/30) before dinner. In this study, the dose was adjusted to achieve an FPG level <110 mg/dL. (112) Insulin-naive subjects were started with 12 U of premixed insulin at dinner, while those previously on basal insulin received 70 to 100% of their total daily insulin as a predinner biphasic insulin aspart 70/30 injection. At the end of a 16-week adjustment period, subjects whose A1C was still >6.5% were given an additional injection of premixed insulin analog at breakfast, starting with a dose of 3 to 6 U of insulin. Following another 16-week adjustment period, those subjects whose A1C was still not at goal ([less than or equal to]6.5%) entered the final phase of the study at which time they were started on 3 U of premixed insulin analog at lunch and the dose adjusted based on postprandial values (see Table 3). (112) Using this strategy, 41% of subjects on a once-daily, premixed analog injection reached the ADA target (A1C <7%), while 70% and 77% of subjects reached goal on twice-daily and thrice-daily premixed analog, respectively, using an intent-to-treat analysis.

For those subjects whose A1C target has still not been achieved on basal-plus or premixed analog therapy, progression to full basal/bolus insulin replacement may be warranted (Fig. 2). Selecting initial basal and prandial insulin doses often requires an estimation of the total daily dose of insulin (TDD) needed by a particular patient. If the patient is already using insulin, clinicians can derive the TDD (U/d) by calculating the total insulin dose (in units) injected in a 24-hour period. Alternatively, the initial TDD may be calculated by multiplying the patient's current weight in kilograms by a factor of 0.5 U/kg/d. Once a starting TDD is identified, that amount of insulin is divided into 50% basal insulin coverage (glargine, detemir, or NPH) and 50% prandial insulin coverage (10-20% at each meal) in the form of a rapid-acting insulin analog or regular human insulin. In addition, a correction (supplemental) scale can be derived by dividing 1800 by the patient's TDD (rule of 1800). The result estimates the fall in blood glucose per unit of rapid-acting insulin. Finally, the patient should be given a preprandial blood glucose target to implement the correction scale. To achieve an A1C level <7%, the preprandial blood glucose target should be <130 mg/dL. To optimize insulin dosages and glycemic control, the patient's SMBG FPG values should be used to adjust the basal component, while the prelunch, predinner, and bedtime values should be used to adjust the morning, noon, and dinner prandial doses, respectively.

The approach we propose for the management of type 2 diabetes is based on the concept of replacement and/or enhancement of basal and prandial insulin secretion and action. In the setting of advanced [beta]-cell deficiency, replacement will take the form of insulin therapy, with rapidly absorbed formulations to cover prandial needs and to correct hyperglycemia and formulations with a protracted absorption to cover insulin needs between meals, overnight, and during periods of fasting. While optimal glycemic control will reduce the risk of microvascular (predominantly) and macrovascular complications, the proper management of type 2 diabetes requires aggressive treatment of hypertension (especially with renin-angiotensin system blockade), lipid abnormalities (especially with the use of statin drugs), and other risk factors for cardiovascular disease, such as smoking, inactivity, and obesity. Aspirin therapy, when not contraindicated, is another simple and cost-effective intervention for reducing cardiovascular events.

[FIGURE 2 OMITTED]

Conclusions

Current approaches to managing type 2 diabetes that delay the use of insulin often fail to provide effective glycemic control. Insulin is the most effective therapy available for managing hyperglycemia, and recent evidence suggests that initiating insulin earlier in the course of type 2 diabetes may provide important benefits, such as improved glycemic control, which may prevent or delay the development of diabetes-related complications.

Although the early initiation of insulin therapy may have significant benefits, there is considerable resistance to initiating insulin therapy in type 2 diabetes because of concerns about injections, hypoglycemia, weight gain, and the challenges involved in implementing insulin therapy. The use of new insulin analogs and premixed insulin analogs, which may be safer, simpler, and more effective than traditional human insulin regimens, may help alleviate some of these concerns and encourage the earlier use of insulin therapy.

Patients who have not reached their glycemic targets while taking OADs have several options for insulin therapy. Assessments of FPG and PPG or data from SMBG should be used to individualize treatment by determining the most appropriate therapy for a particular patient. For patients with elevated FPG, adding basal insulin is simple and effective. For patients with substantially elevated PPG, adding premixed insulin or basal-bolus therapy may be more appropriate. Regardless of the approach, the ultimate goal of insulin replacement therapy remains to optimize glycemia, minimize complications, and provide maximum flexibility, therapeutic simplicity, and QOL.

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112. Garber AJ, Wahlen J, Wahl T, et al. Attainment of glycaemic goals in type 2 diabetes with once-, twice-, or thrice-daily dosing with biphasic insulin aspart 70/30 (the 1-2-3 study). Diabetes Obes Metab 2006;8:58-66.

Luigi Meneghini, MD, MBA 

From the Eleanor and Joseph Kosow Diabetes Treatment Center, Diabetes Research Institute, Miami, FL.

Reprint requests to Luigi Meneghini, MD, MBA, Associate Professor of Clinical Medicine, University of Miami Miller School of Medicine, Director, Eleanor and Joseph Kosow Diabetes Treatment Center, Diabetes Research Institute, 1450 NW 10th Avenue, Miami, FL 33136. Email: [e-mail]

Dr. Meneghini has received research support from Amylin, Merck, Novo Nordisk, and Sanofi-Aventis. He is on an advisory panel for NIPRO Systems and holds stock in Amylin. He belongs to the Speakers' Bureaus for Amylin. Eli Lilly, Glaxo SmithKline, Medtronic, Novo Nordisk, Pfizer, and Sanofi-Aventis. Dr. Meneghini has no commercial or proprietary interest in any drug or device mentioned in this article.

Accepted October 16, 2006.

RELATED ARTICLE: Key Points

* Current approaches to managing type 2 diabetes that delay the use of insulin often fail to provide effective glycemic control.

* Initiating insulin earlier in the course of treatment may improve glycemic control, which may prevent or delay the development of diabetes-related complications.

* The greater safety and convenience of insulin analogs compared to regular human insulin therapies may help reduce resistance to initiating insulin among patients and practitioners and facilitate the earlier use of insulin therapy.

Table 1. Weekly adjustment algorithm for basal insulin therapy (the
Treat-to-Target Study)

Titration regimen: start 10 U/day at bedtime

FPG (mg/dL)  [up arrow] Insulin dose (U/day)

  100-120    2
  121-140    4
  141-180    6
  >180       8

Copyright 2003 American Diabetes Association, from Diabetes Care
2003;26:3080-3086; modified with permission from the American Diabetes
Association. (76)
Combination OAD plus bedtime glargine or NPH. The treat-to-target FPG
was [less than or equal to]100 mg/dL. Mean of self-monitored FPG values
from preceding 2 days were used. Exceptions: (1) no increase in dosage
if FPG <72 mg/dL (4.0 mmol/L) was documented at any time in the
preceding week and (2) small insulin dose decreases (2-4 IU/day per
adjustment) were allowed if severe hypoglycemia (requiring assistance)
or plasma-referenced glucose <56 mg/dL was documented in the preceding
week.

Table 2. Pharmacodynamic properties of available insulin preparations

                       Onset of                          Duration
Insulin                action         Peak action        of action

Regular                30-60 minutes  2-3 h              8-10 hours
Aspart                 5-15 minutes   30-90 minutes      4-6 hours
Lispro                 5-15 minutes   30-90 minutes      4-6 hours
Glulisine              20 minutes     90 minutes         5.3 hours
NPH                    2-4 hours      4-10 hours         12-18 h
Glargine               2-4 hours      4 hours (peak not  Up to 24 hours
                                        pronounced)
Detemir                0.8-2 hours    3-9 hours (peak    Up to 24 hours
                                        not pronounced)
Humulin/Novolin 70/30  0.5-1 hours    2-16 hours         18-24 h
Humalog Mix 75/25      15-30 minutes  0.5-2.5 hours      Up to 24 hours
Novolog Mix 70/30      10-20 minutes  1-4 hours          Up to 24 hours

Compiled from Kamal, et al (104); Plank, et al (105); Humalog Mix 75/25
[package insert] (106); Levemir [package insert] (107); Novolog Mix
70/30 [package insert] (108); LaSalle (109); Daugherty. (110)

Table 3. Weekly adjustment algorithm for premixed insulin analog therapy
(BIAsp 30). Reprinted with permission from Garber, 2006 (112)

Predinner dose
  Prebreakfast SMBG (mg/dL)    <80  80-110     111-140    141-180  >180
  Adjustment of predinner      -3   No change  +3         +6       +9
    dose (U)
Prebreakfast dose
  Predinner SMBG (mg/dL)       <80  80-110     111-140    141-180  >180
  Adjustment of prebreakfast   -3   No change  +3         +6       +9
    dose (U)
Prelunch dose
  2-hours post-lunch SMBG           <100       100-140    141-180  >180
    (mg/dL)
  Adjustment of prelunch dose       -3         No change  +3       +6
    (U)

Titration was followed as specified unless an episode of hypoglycemia
occurred. Predinner BIAsp 30 doses were titrated based on prebreakfast
blood glucose values. Prebreakfast BIAsp 30 was adjusted based on
predinner blood glucose values. Prelunch insulin was adjusted according
to postlunch blood glucose values. Reprinted with permission from
Garber, 2006.