Contents
Contributors
Search

· Although the treatment options for Type 2 diabetes have expanded rapidly in recent years with the development of new oral therapies, the abilities of these agents to lower blood glucose to reach and sustain glycemic targets is limited

· There are many oral agents now available for the treatment of Type 2 diabetes, including insulin secretagogues (sulfonylureas and non-sulfonylureas), biguanides (metformin), thiazoledinediones and α-glucosidase inhibitors (1; 2)

· Type 2 diabetes is a progressive disease with worsening hyperglycemia due mainly to a relentless decline in insulin secretion (3; 4)

· As our understanding of the natural history and progressive course of Type 2 diabetes increases, so does the need for more effective blood glucose lowering therapies

· Insulin has been viewed traditionally as a last resort, to be used only when all other treatment options have been exhausted

· However, significant improvements in insulin therapy are beginning to remove the barriers to initiation of insulin replacement in Type 2 diabetes

· Insulin should now be viewed as a valuable therapeutic tool for early intervention, to attain and maintain target levels of blood glucose control

· The transition from combination oral therapy to insulin treatment can be achieved using a structured titration regimen that patients can easily follow, based on self blood glucose monitoring to achieve defined glycemic targets

· The purpose of this chapter is to review the increasingly important role of insulin in the management of Type 2 diabetes and to provide practical guidelines for insulin therapy

· There are two defects that, together, cause Type 2 diabetes: impaired insulin secretion with progression towards insulin deficiency and insulin resistance (2)

· Impaired insulin secretion is a result of initial beta cell dysfunction and subsequent insulin deficiency, while insulin resistance results in increased hepatic glucose production and reduced peripheral glucose uptake (2)

· There is evidence that beta cell dysfunction begins prior to the onset of Type 2 diabetes and, indeed, can predict the progression from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to Type 2 diabetes (4)

· The United Kingdom Prospective Diabetes Study (UKPDS) demonstrated an inexorable decline in beta cell function (and, therefore, insulin secretion) over time in patients with Type 2 diabetes, despite oral therapy, indicating a clear need for insulin therapy in these patients if blood glucose control targets are to be met and maintained (3)

· Short-term intensive therapy has been shown to improve insulin resistance, possibly by correcting glucotoxicity and lipotoxicity (5-9)

· Furthermore, the reduced strain on the beta cell by insulin therapy can potentially induce ‘beta cell rest’, which results in increased insulin secretion (10; 11)

· Clinical support for this ‘beta cell rest’ hypothesis comes from the observation that a small group of newly diagnosed patients with Type 2 diabetes treated intensively with insulin for two weeks achieved and maintained normoglycemia for an extended period, without any further therapy (12)

· One could speculate from this observation that earlier initiation of insulin therapy – perhaps even from disease onset – could preserve beta cell function and, thus, insulin secretion, which could prevent disease progression and/or improve glycemic responses to supplemental oral treatment if needed

· Insulin resistance is a major pathogenic defect in Type 2 diabetes and correlations with obesity and hyperinsulinemia have resulted in misconceptions of the role of exogenous insulin therapy (13)

· Despite concerns that insulin treatment may, therefore, worsen insulin resistance, glucose clamp studies have demonstrated that short-term intensive insulin therapy actually improves insulin resistance (Figure 1) (5-7)

Figure 1. Improving Insulin Resistance with Intensive Insulin Therapy in Type 2 Diabetes. Glucose disposal rates pre- and post-intensive insulin therapy were evaluated by glucose clamp (5-7)

· In all of the studies depicted in Figure 1, the insulin treatment period was 2–4 weeks and the insulin dose needed to attain near-normoglycemia was high (>100 IU per day)

· There was an increase in insulin sensitivity of almost 50% with insulin treatment, which is indicative of decreased insulin resistance

· Similar intensive insulin therapy for 12 weeks in patients with Type 2 diabetes resulted in an impressive reduction in A1c from 10.1% at baseline to 6.6% (9)

· In this study, and those described above, insulin resistance was not corrected fully, but was, nevertheless, drastically reduced

· There is a well known epidemiologic association between endogenous hyperinsulinemia and the incidence of coronary heart disease in non-diabetic individuals (14)

· Despite concerns that hyperinsulinemia may be related to increased cardiovascular risk, evidence from the Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study demonstrated that exogenous insulin had a cardioprotective effect following acute myocardial infarction (MI); in this study, long term intensive insulin therapy had substantial cardiovascular benefits, resulting in a significant relative risk reduction in mortality by 28% versus conventional therapy at an average of 3.4-year follow-up (Figure 2a) (15; 16)

· This benefit was even more pronounced in patients who were insulin-naïve prior to MI, where the relative risk reduction for mortality was 51% with intensive insulin therapy (Figure 2b) (16)

· These results indicate that, in patients with Type 2 diabetes, particularly those who have a high cardiovascular risk, insulin therapy may be very relevant and needs to be seriously considered. Further long term cardiovascular outcome studies are underway to confirm these findings

Figure 2. Cardiovascular Benefit Of Intensive Insulin Therapy Post-MI In The DIGAMI Study. Patients (n=620) who had experienced MI were randomized to either intensive insulin therapy (48-hour continuous infusion followed by four-times daily insulin injections for up to 5 years) or conventional therapy (according to physician judgement). Panel A shows the total population; panel B shows insulin-naïve patients (n=272) [Taken from Malmberg et al, BMJ 314:1512–1515, 1997] Permission requested.

· Furthermore, the UKPDS provided no evidence of an increased incidence of atherosclerotic events in people with Type 2 diabetes who were treated with insulin versus those who did not receive insulin (17)

· Over the years, multiple barriers to insulin therapy, such as fear of needles, limitations of insulin formulations, complexity of regimens and misconceptions relating to the significance of insulin with respect to complications, have challenged the acceptance and the effective use of insulin replacement therapy in Type 2 diabetes (13)

· Despite evidence that insulin therapy may be most beneficial in patients with Type 2 diabetes as outlined above, physicians also have numerous barriers to insulin therapy including (Table 1):

– Exaggerated concern that insulin therapy may cause significant weight gain in patients with Type 2 diabetes

– Valid concerns that the risk of hypoglycemia will be increased, which is partly related to the limitations of traditional insulin preparations

– Misconceptions from the epidemiologic non-interventional studies about endogenous insulin (not exogenous insulin therapy) as a factor that may increase cardiovascular risk

– Limited resources and time constraints to instruct patients with Type 2 diabetes how to inject and adjust insulin therapy

– Complex insulin strategies starting with multiple insulin injections

– Skepticism that patients will not accept insulin and will not follow titration algorithms to achieve stringent glycemic targets

· These barriers are discussed in detail below

· Initiation of insulin therapy is, typically, associated with weight gain, which correlates with increasingly better glycemic control

· This increase in weight in the range 2–5 kg may be partly explained by the fact that patients often maintain their previous inappropriate dietary regimens but no longer experience caloric loss from glycosuria, as a result of improved glycemic control (18)

· However, this weight gain has been shown to be insufficient to increase cardiovascular (CV) risk factors (e.g. blood pressure, lipid patterns) in obese patients with Type 2 diabetes; indeed, some risk factors were actually improved with insulin therapy (19-22)

· In addition, the weight gain associated with insulin therapy can be minimized by reducing caloric intake and increasing physical activity as well as combining with metformin, as will be discussed below

· Hypoglycemia is the single most important limiting factor to increasing and adjusting insulin doses to attain satisfactory glycemic control (13)

· Hypoglycemia risk is dependent on a number of factors, including age, weight, duration of diabetes, severity of insulin resistance, consistency of caloric intake, history of recurrent hypoglycemia, alcohol consumption, physical activity, degree of diabetic neuropathy and awareness of hypoglycemia

· It is clear that there is an extremely strong correlation between the level of glycemic control achieved in Type 1 diabetes and the resulting level of severe hypoglycemia, as evidenced by data from the Diabetes Control and Complications Trial (DCCT; Figure 3) that demonstrated a three fold increase in hypoglycemia with tight control (23)

· The UKPDS showed that, in patients with Type 2 diabetes, most incidents of hypoglycemia were mild in severity; severe hypoglycemia occurred in only 2–3% of patients each year (17; 24)

· However, it should be remembered that in the majority of studies in Type 2 diabetes, patients do not reach near-normoglycemia; therefore, it is entirely possible that hypoglycemia, severe or otherwise, would become more common as more patients are aggressively managed following recommended guidelines to achieve better glycemic control treating to target A1c levels (13)

Figure 3. Correlation Between Tighter Glucose Control (Lower Hemoglobin A1c) And Severe Hypoglycemia. [Taken from Am J Med 90:450–459, 1991] Permission requested.

· A comparison of the kinetics of the insulin preparations available for clinical use is described in Table 2 (13); this includes traditional formulations and new analogs of human insulin

· Regular human insulin is less than ideal for post-prandial glucose control:

– The slow onset of action necessitates administration 20–40 minutes before meals, putting patients at risk of pre-meal hypoglycemia if the meal is delayed

– The duration of action extends beyond the duration of endogenous insulin activity, therefore, the risk of hypoglycemia is increased; this encourages between-meal snacking, which promotes weight gain in Type 2 diabetes

· Insulin lispro and aspart are two short-acting insulin analogs with increased rate of dissociation into insulin monomers resulting in rapid absorption profiles that allow for more physiologic replacement of mealtime insulin requirements

· These two analogs developed for post-prandial blood glucose control,match normal mealtime insulin secretion patterns far more closely than does exogenous regular human insulin, with a more rapid onset of action, an earlier peak of activity and a shorter duration of action (25; 26)

· Clinical experience has shown that these properties result in improved post-prandial glucose control (26-32). Insulin glulisine is another fast-acting analog in clinical development that appears to have similar pharmacokinetic and pharmacodynamic profiles as insulin lispro and aspart

· However, their rapid waning of activity places greater dependence on sufficient interprandial basal insulin to maintain blood glucose control

· With increasing use of lispro and aspart, there is a growing need for protracted-acting insulins that afford adequate and reliable glycemic control in the post-absorptive state

· Of the insulin formulations used traditionally for basal insulin replacement, NPH insulin and lente are intermediate-acting, with durations of action considerably less than 24 hours, and pronounced peaks in activity within a few hours of administration

· Ultralente, although longer acting, is subject to considerable variation in dosing, with erratic peaks in activity

· These limitations leave patients at increased risk of unpredictable hypoglycemia

· Insulin glargine is the first clinically available long-acting analog of human insulin (33)

· Insulin glargine (LANTUS) results from amino acid changes that shift the iso-electric point of the insulin molecule towards neutral, making it soluble at slightly acidic pH and less soluble at the physiologic pH of the subcutaneous tissue leading to microprecipitation which forms the basis for its protracted duration of action

· In contrast to the traditional intermediate- and long-acting insulin preparations described above, insulin glargine has a 24-hour flat time–action profile with no pronounced peaks

· This profile resembles that of continuous subcutaneous insulin infusion (CSII), which is considered to be the ‘gold standard’ of basal insulin replacement therapy (Figure 4) (34-36)

Figure 4. Plasma Glucose Concentrations after Subcutaneous Injection. Results of a glycemic clamp study. [Taken from Lepore et al, Diabetes 49:2142–2148, 2000] Permission requested

· Furthermore, the duration of action of insulin glargine is more prolonged than those of ultralente and NPH insulin, at approximately 24 hours (Figure 5)

· Consistent with its slow absorption rate and duration of activity, insulin glargine allows for a once daily administration with no peak of action and less variability than NPH

· Clinical experience with insulin glargine has demonstrated that this pharmacokinetic and pharmacodynamic profile translates into a reduced risk of nocturnal hypoglycemia, without compromising glycemic control, particularly in Type 2 diabetes (37-43)

· An additional benefit for this analog is the consistency of absorption irrespective of injection site (arm, leg or abdomen) (44)

Figure 5. Time–Action Profile Of Insulin Glargine Following Subcutaneous Injection. Glycemic clamp study. [Taken from Lepore et al, Diabetes 49:2142–2148, 2000] Permission requested.

· Insulin detemir is another long-acting insulin analog in final stages of clinical development and testing that is expected to be commercially available soon (45)

· The retardation principle for this analog is fatty acylation of the insulin molecule, which promotes albumin binding (46)

· Glycemic clamp studies have shown that, like insulin glargine, the profile of detemir is flatter than that of NPH insulin (47)

· However, the duration of action has been shown to be less than 24 hours at therapeutic doses, suggesting that this analog may not be suitable for once-daily dosing and will deliver its best effect with a twice-daily regimen (47)

· Administration of insulin by injection is inherently a barrier to use in patients with Type 2 diabetes, who are likely to have been taking only oral agents for several years before insulin therapy is initiated

· Developments in delivery devices such as pens that reduce the discomfort of injection and simplify the administration of insulin have addressed this issue (48; 49)

· Inhaled insulin is another delivery option that would remove the skin barrier of injection fear completely

· There is already proof of concept reported for the use of inhaled insulins for post-prandial blood glucose control (50; 51)

· However, this form of insulin delivery is still in the advanced clinical developmental stages, and longer studies assessing the impact of inhaled insulin on a number of therapeutic scenarios with particular attention to safety and efficacy are awaited with great interest

· The association between insulin resistance (with the resulting endogenous hyperinsulinemia), central obesity, hypertension and dyslipidemia, all of which are known CV risk factors (14; 52), has raised some concern among physicians that insulin therapy may increase CV risk

· However, in fact the opposite is probably true: insulin may have beneficial cardioprotective effects in patients with Type 2 diabetes (see section 2.3)

· Insulin replacement therapy should ideally mimic the physiologic insulin secretion patterns that are observed in response to 24-hour fasting post-absorptive and postprandial glucose profiles (Table 3)

· The basal–bolus concept aims to mimic as closely as possible this complex physiologic daily pattern of insulin secretion in healthy individuals (Figure 6) (53)

Figure 6. Normal Physiologic Insulin Secretion. [Taken from Lee and Zinman, Diabetes Reviews Vol 6; 73–88, 1998] Permission requested.

· The role of the basal insulin in basal–bolus regimens is to suppress hepatic glucose production and lipolysis in the post-absorptive state between meals and overnight

· The role of the bolus insulin is to limit hyperglycemia immediately after meals

· The basal–bolus concept is used routinely in Type 1 diabetes, but is also applicable to Type 2 diabetes, since both prandial and interprandial as well as fasting blood glucose levels are elevated in Type 2 diabetes (Figure 7)

Figure 7. Prandial And Interprandial Blood Glucose In Type 2 Diabetes Versus Healthy Individuals. [Taken from Riddle, Diabetes Care 16n:676–686, 1990] Permission requested.

Earlier Insulin Replacement…When?

· The UKPDS Glucose Study 2 (UKPDS 57) provided strong evidence that the immediate addition of a basal insulin regimen when sulfonylurea monotherapy is unable to maintain fasting plasma glucose (FPG) <108 mg/dL substantially improves glycemic control, without significantly increasing the risk of hypoglycemia (24)

· In this long-term study, approximately 50% of patients receiving insulin added to a sulfonylurea achieved a median A1c level of 6.7% at 6 years, which is an important translational message to physicians as an effective management strategy to sustain glycemic targets in clinical practice

· Most importantly, in keeping with the results of the UKPDS Glucose Study 2, the concept of insulin as expected therapy in the management of Type 2 diabetes should be introduced at the time of diagnosis, so the patient knows and understands better the role of insulin and will eventually accept insulin therapy more openly when overtime glycemic control can not be adequately maintained by oral agents

· The mental barrier and misconceptions that insulin therapy is a sign of failure, or indicative that finally the Type 2 diabetes “has worsened or has become serious”, need to be permanently dispelled

· At the present time, a practical approach to encourage earlier insulin initiation is that insulin therapy should be considered if the A1c levels remain >7%, despite maximized oral agent therapy and lifestyle intervention

· Maximizing oral therapy could be one, two or three oral agents according to the patients’ tolerance and side effect profile

· Conventionally, maximized oral agent therapy is a combination of three oral agents; however, the effectiveness in reaching and sustaining A1c targets is relatively limited as shown below (Table 4)

Limitations of Conventional Pre-Mixed Formulations

· The use of ‘pre-mixed’ insulin preparations, such as 70/30 or 75/25, using NPH insulin plus regular, lispro or aspart do not provide enough flexibility and are seldom effective for reaching glycemic targets

· Additional limitations of pre-mixed insulins are listed in Table 5:

· The twice-daily ‘split-mixed’ regimen consists of a morning and evening mix of NPH insulin and a short-acting insulin

· The short-acting insulin (regular, lispro or aspart) in the morning covers the time between breakfast and lunch, whereas the intermediate-acting NPH insulin peaks around noon and covers the afternoon until dinnertime

· The second ‘split-mixed’ dose administered at the evening meal, provides insulin coverage between the dinner and bedtime interval (short-acting insulin component) and also coverage overnight (NPH insulin component); this overnight NPH insulin dose often peaks during the late night

· Furthermore, these two insulins have overlapping peaks, which can occur at any time, resulting in frequent periods of inappropriate hyperinsulinemia and a propensity to hypoglycemia, which can lead to frequent snacking

· The 70/30 pre-mixed NPH/regular insulin, 70/30 pre-mixed NPH/aspart insulin or 75/25 pre-mixed NPL/lispro have been traditionally used. However, the fundamental problem with these preparations is the rigidity of the supplementation and lack of flexibility for specific insulin adjustments because the two insulins are adjusted at the same time based on self-blood glucose monitoring. These pre-mixed insulins often result in periods of excessive hyperinsulinemia with increased risk of hypoglycemia which is a major limitation for reaching glycemic targets (Table 6)

Initiating Insulin Therapy with Basal Insulin

Rationale for Starting with Basal Insulin as Add-on to Oral Therapy

· Basal insulin replacement therapy covers approximately 50% of the daily insulin needs and should ideally mimic the physiologic insulin secretion patterns to control the 24-hour post absorptive glucose profiles by suppressing hepatic glucose production overnight, during fasting and during prolonged periods between meals

· A single evening or bedtime injection of basal insulin with continued use of one or more oral agents has been shown to lower fasting hyperglycemia, with a beneficial carryover effect on glycemic levels later in the day; this results in significant improvements in A1c levels

· One explanation for this outcome is that basal insulin can improve overnight and fasting glucose control enough to decrease glucotoxicity, allowing oral agents to have their full effect on modulating and increasing insulin secretion for mealtime control

· The cumulative impact is improved glycemic control with a reduced need for exogenous insulin as endogenous insulin secretion increases as a result of preserved β cell function and possible β cell rest (13; 57)

· This simple approach overcomes the complexity of insulin regimens in Type 2 diabetes, and is perhaps the most practical and most acceptable way to initiate insulin therapy, by just adding an evening basal insulin replacement in patients who are no longer responding to oral agents

· There are numerous benefits in adding a basal insulin replacement while maintaining the use of oral antidiabetic agents:

– Only one daily insulin injection may be required, thus keeping the treatment regimen simple, and the mixing of different insulin preparations is not needed

– Easy titration in a slow and, therefore, safer way but on a consistent basis according to fasting blood glucose targets

– Administration with an insulin pen facilitates and enhances patient acceptance and adherence to insulin therapy

– Eventually, basal insulin used in combination with oral antidiabetic agents will require a lower total insulin dose because of the synergy or complementary effects of individual oral therapies

· These advantages result in a greater improvement in glycemic control compared with the use of oral antidiabetic agents alone with only limited weight gain

· The ability to add a single basal insulin dose to the therapeutic regimen of Type 2 diabetes patients acts as a simple and effective ‘bridge strategy’ that will be more acceptable to many patients and will facilitate and enable them to overcome their resistance to insulin therapy

· Eventually, if the A1c levels remain >7% despite the use of evening basal insulin in combination with oral therapy , and as long as the fasting glucose levels are normal, then further benefit can easily be obtained by progressively adding pre-meal lispro or aspart insulin to the main meals to control postprandial hyperglycemia

· There is much clinical evidence to support the safety and efficacy of the addition of basal insulin to oral agents, which is summarized in the next section

· The synergistic effects of basal insulin added in combination with insulin secretagogues and insulin sensitizers have been demonstrated in a number of studies adding once-daily ultralente to sulfonlyureas, bedtime NPH insulin to glipizide or glyburide, dinnertime 70/30 mix to glimepiride, or bedtime NPH insulin to various oral agents including metformin

· Conclusion: Addition of long-acting ultralente to sulfonylurea effectively restores normoglycemia, particularly when used early in disease progression, without increasing hypoglycemia or weight gain

· Conclusion: Addition of bedtime NPH insulin to sulfonylurea effectively improves glycemic control and overcomes secondary sulfonylurea failure

· Conclusion: Proof of concept of the effectiveness and value of combination oral agents and basal insulin therapy. Bedtime NPH insulin + metformin afforded greater improvement in glycemic control with less weight gain. However, the combination of sulfonylurea and bedtime NPH insulin was slightly less effective but with less hypoglycemia, probably owing to lower insulin doses

· Insulin glargine, a long-acting human insulin analog with a flat profile of action, is being increasingly used to treat Type 2 diabetes patients

· Glargine may be especially suited as a supplemental basal insulin added to oral therapy owing to a lower risk of nocturnal hypoglycemia compared with NPH insulin (42; 43)

· The “One Pill-One Shot” study compared combinations of the oral agent glimepiride with bedtime NPH insulin versus glimepiride with bedtime or morning insulin glargine in patients with Type 2 diabetes previously treated with one or two oral agents(61)

· All three groups were on glimepiride but the risk of nocturnal hypoglycemia was lower in the groups with morning insulin glargine (17%) and bedtime insulin glargine (23%) than with bedtime NPH insulin (38%)

· A1c levels improved by –1.24% with morning insulin glargine, –0.96% with bedtime insulin glargine and –0.84% with NPH insulin over the 6 month study but it is conceivable that the results could have been more effective if metformin or an insulin sensitizer had been used in combination with the sulfonylurea

· The ‘Treat-to-Target’ study, which compared basal insulin replacement therapy with either bedtime insulin glargine or NPH insulin added to oral combination therapy also in insulin-naïve patients, revealed the efficacy of these insulins administered using a structured titration algorithm for actively adjusting insulin doses to achieve fasting plasma glucose (FPG) levels <100 mg/dL and reaching A1c levels <7% (62)

· A1c values decreased from 8.6% at baseline to 6.9% by the end of the 6 month study with both insulins, successfully achieving A1c targets in almost 60% of patients

· However, the patients receiving insulin glargine experienced a 44–48% risk reduction in nocturnal hypoglycemia compared with those receiving NPH insulin (Figure 8)

· Furthermore, significantly more patients in the insulin glargine group (33%) reached target A1c ≤7%, without a single episode of documented nocturnal hypoglycemia, compared with those in the NPH insulin group

Figure 8. Comparison of hypoglycemia profiles with NPH insulin versus insulin glargine in combination with oral agents, in patients with Type 2 diabetes. [Adapted from Riddle et al, Diabetes Care 26:3080-3086, 2003] Permission requested.

· Type 2 diabetes patients treated to glycemic target are always at increased risk of hypoglycemia and thus any therapeutic tool that has less risk of hypoglycemia is a welcome pharmacologic addition

Rationale for Initiation of Bolus Insulin as Add-On to Oral Therapy

· The rationale for initiation of insulin therapy with mealtime insulin supplementation is to improve postprandial hyperglycemic peaks while continuing sensitizing agents such as metformin or a glitazone with or without sulfonylureas

· Initiating a bolus insulin for patients with Type 2 diabetes for whom oral therapy is no longer able to maintain normoglycemia has been shown to be effective with three injections of insulin lispro added to sulfonylurea (63)

· This study showed that the addition of preprandial insulin lispro resulted in lower A1c (7.6%) compared with the addition of bedtime NPH insulin or the addition of metformin in a 12-week time period

· The morning FBG was lowest in the bedtime NPH insulin group; however, postprandial glucose was lowest in the insulin lispro + sulfonylurea group

· The feasibility of using inhaled insulin to initiate bolus insulin therapy has been demonstrated in Type 2 diabetes patients who did not maintain A1c <8.0% on combination oral therapy (64)

· This large study demonstrated that patients receiving combination oral therapy together with inhaled insulin experienced the greatest decrease in A1c (-1.9%) compared with those receiving inhaled insulin alone (-1.4%) or those patients who continued therapy with oral agents alone (-0.2%) (64)

· Further long-term studies to examine the pulmonary safety and sustained efficacy of inhaled insulin are required before FDA approval and it is made commercially available to patients

· Initiating insulin as bolus therapy in patients with Type 2 diabetes is not optimal owing to the need for multiple premeal injections, which means the regimen is more complex and, therefore, less attractive to Type 2 diabetes patients compared with introducing a single basal insulin injection

· The potential availability of inhaled insulin some time in the future may enable bolus insulin supplementation in Type 2 diabetes patients to become a reality, as this type of administration is likely to be more acceptable to patients

· In light of the increasing tendency to initiate insulin therapy much earlier in the natural clinical progression of Type 2 diabetes, there is a need for practical guidelines to enable general physicians to administer insulin effectively and safely

· As discussed above, probably the most practical way to initiate insulin therapy in Type 2 diabetes is the addition of an evening basal insulin supplement to ongoing oral therapy

· The efficacy, safety and ease of this strategy make it especially accommodating to the needs of time-pressed clinicians in general practice, who manage the vast majority of patients with Type 2 diabetes

· Early initiation of basal insulin, as a supplement to ongoing oral therapy, is a simple and effective strategy, which may help patients with Type 2 diabetes overcome their resistance to insulin therapy

· This approach also alleviates key patient concerns about insulin therapy, dispelling the myths that it is too complex and poses a dangerously high risk of hypoglycemia

· Insulin glargine (LANTUS), by virtue of its long duration, flat profile of action and reduced risk of nocturnal hypoglycemia, has the potential to enable a simple initiation of insulin therapy

· Insulin glargine was initially studied using a bedtime once-daily administration but, as a result of its pharmacokinetic profile, it could theoretically be given at any time of the day (although at the same time every day) (65)

· Effective titration of basal insulin while continuing oral therapy, can be achieved on the basis of self-monitored FBG levels

· The dose increase would depend on the FBG according to a titration algorithm that is continuously followed by the patient to sustain glycemic targets

· If levels are elevated above a pre-defined target FBG level, usually <100 mg/dL, as an average from two or three consecutive days, the insulin dose is then increased, provided nocturnal hypoglycemia has not occurred and/or the FBG is not <72 mg/dL

· This method of titration was employed in the Treat-to-Target study with a pre-defined FBG treatment target of 100 mg/dL (62); the starting dose of basal insulin was a once-daily evening dose of 10 IU and a weekly forced titration schedule as shown in Table 10

· Alternatively, an even simpler titration algorithm that is well accepted and facilitates the ‘empowerment’ of the patients to maintain patient-driven basal insulin adjustments to reach and sustain FBG <100 mg/dL, as long as there are no symptoms or evidence of hypoglycemia, is as follows:

· Oral agents can be of value at this point, depending on individual patient needs and side effect profile (Table 12)

· Metformin therapy can be continued in parallel with basal insulin therapy in order to control weight gain as long as renal impairment and congestive heart failure (CHF) are not present

· A glitazone may be used to reduce insulin resistance and potentially preserve beta cell function, as long as there is no evidence of substantial weight gain and fluid retention

· Secretagogues can be potentially useful to enhance endogenous insulin secretion, especially after glucotoxicity has been corrected and following ‘beta cell rest’ with exogenous insulin; the response to sulfonylureas or meglitinides may control postprandial hyperglycemia better

· Over time, insulin regimens will need to be intensified in response to disease progression as determined by the lack of attainment or the loss of sustained glycemic targets

· As Type 2 diabetes progresses, and beta cell function declines, there will be an eventual need to intensify therapy as oral agents begin to lose the ability to control postprandial hyperglycemia

· When a target FPG of <100 mg/dL has been achieved and the A1c is still above 7.0%, further increments in the dose of basal insulin glargine may be employed; however, this approach could result in an increased risk of hypoglycemia

· For these patients, additional insulin, basal or prandial, can be incorporated into the treatment regimen as shown in Table 12, depending on the basal insulin type used

· Pre-mixed insulin preparations do not provide the necessary flexibility to achieve the recommended levels of glycemic control and should preferably not be considered when other insulin therapies are available

· The next step, therefore, is to introduce a preprandial fast-acting insulin analog at the main meal in the first instance, which should result in an improvement in postprandial glucose levels

· Multiple daily insulin regimens (MDI) using short-acting insulin analogs (lispro or aspart) at the main meal or at each meal, to closely match physiologic prandial insulin patterns, can further optimize the once-daily basal insulin glargine therapy, which provides a more predictable basal control than NPH insulin with less risk of nocturnal hypoglycemia

· The titration schedule should be based on self-monitored blood glucose levels according to some predetermined postprandial glucose levels; controversies still exist regarding the target 2-hour postprandial levels that are usually in the 140–180 mg/dL range

· By titrating basal and bolus insulin separately, maximum treatment flexibility is achieved

· Using this approach, multiple dose insulin (MDI) therapy is progressively introduced to the patient in order to ultimately mimic normal physiology (Table 13)

· This practical and simple strategy outlined above should enable Type 2 diabetes patients to reach and sustain defined glycemic targets, facilitating the translation of clinical research studies into clinical practice

· Insulin therapy in Type 2 diabetes has been viewed traditionally as a last resort used only when all other therapeutic options have been exhausted

· Physicians must, therefore, view insulin as a vital therapeutic tool for attaining and sustaining treatment goals, not as a sign of treatment failure

· A shift in the treatment paradigm for Type 2 diabetes is needed, towards the earlier use of insulin to preserve beta cell function to maintain long term near-normoglycemic control only limited mainly by hypoglycemia

· Hopefully, the simple strategies reviewed above will evolve to become the standard of care to benefit patients with Type 2 diabetes. The early use of supplemental basal insulin glargine to oral combination therapy to reach A1c targets and if needed, systematically adding a meal-time short-acting analogue lispro or aspart insulin to control postprandial hyperglycemia, has the potential to be widely translated to the primary care settings

· The use of effective insulin pens is increasing and will clearly improve the adherence and compliance of the patients to follow insulin replacement strategies

· In order to maintain good glycemic control in the long term, insulin doses should be continuously titrated to reach treatment glycemic targets, with special consideration always given to hypoglycemia

· With continuing improvements in insulins (both pharmacokinetic properties and delivery routes) and treatment regimens, the ultimate goal of reduced risk of long-term complications through tight glycemic control will be achievable