Type 2 Diabetes—Advancing Insulin Therapy in Patients with Prior Experience of Basal Insulin plus Oral Agents

Where type 1 diabetes is an autoimmune disease characterized by the complete destruction of pancreatic beta cells leading to biological deficiency of insulin, type 2 diabetes is a metabolic disorder of unknown etiology. Patients with type 2 diabetes often experience defects in multiple organs that can lead to a number of pathogenic factors, including reduced insulinmediated glucose transport and increasing resistance in muscle and adipose tissues, increasingly uncontrolled gluconeogenesis, and impaired beta-cell function, causing a progressive decline in pancreatic insulin secretion.

Where type 1 diabetes is an autoimmune disease characterized by the complete destruction of pancreatic beta cells leading to biological deficiency of insulin, type 2 diabetes is a metabolic disorder of unknown etiology. Patients with type 2 diabetes often experience defects in multiple organs that can lead to a number of pathogenic factors, including reduced insulinmediated glucose transport and increasing resistance in muscle and adipose tissues, increasingly uncontrolled gluconeogenesis, and impaired beta-cell function, causing a progressive decline in pancreatic insulin secretion. Because the symptoms of type 2 diabetes are typically milder than those of type 1, the disease can go unnoticed for a number of years before it is diagnosed; the United Kingdom Prospective Diabetes Study (UKPDS) states that at the time of diagnosis individuals have typically lost 50% of their betacell function.¹ Type 2 diabetes therapy should therefore ideally be able to control glucose levels in both fasting and post-prandial states. Although there is no established cure for type 2 diabetes, it is possible to manage the disease and maintain a healthy quality of life through monitoring of health maintenance and adjustment of therapy as needed. This article will outline the current recommendations in treatment of type 2 diabetes, focusing on developments in insulin therapy for treatment-experienced patients.

Initial Treatment
Traditionally, a diagnosis of type 2 diabetes is initially treated with lifestyle interventions such as diet and exercise. Current clinical practice guidelines state that if these methods prove inadequate in controlling glycemic levels, antidiabetic interventions in the form of oral hypoglycemic agents, incretin mimetics, amylin analogs, or insulin become necessary, with further pharmacological adjustments as required.^2–4 Each of the five oral hypoglycemic agents available on the market has distinct mechanisms of action (see Table 1), and should be selected for use as either monotherapy or combination therapy based on efficacy in controlling glycemic levels. A consensus statement from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommends that the biguanide metformin be used as the initial pharmacological therapy alongside lifestyle adjustments following diagnosis.⁴

Failure to achieve glycated hemoglobin (HbA_1c) goals, indicative of poor glycemic control, should prompt considerations for additional medications. Depending on the oral antidiabetic drug used, monotherapy can reduce HbA_1c levels by a maximum of 1–2%,^5,6 and the medicines currently available are unable to simultaneously treat both the secretory deficits and resistance to insulin in type 2 diabetes. At the time of diagnosis, many patients have HbA_1c levels greater than 9.0%; with oral antidiabetics used as monotherapy, many patients are unable to succeed in maintaining their glycemic control below an HbA_1c level of 7.0%—this is significant, as the ADA recommends that HbA_1c levels be <7.0% for most patients,² with the International Diabetes Federation (IDF) and American Association of Clinical Endocrinologists (AACE) recommending an even lower HbA_1c target of 6.5%.^3,7 The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial comparing intensive versus standard blood glucose lowering in patients with type 2 diabetes at high risk for heart disease was prematurely stopped, as patients in the more aggressive treatment cohort attempting to reach HbA_1c levels below 6.0% had increased mortality compared with patients ascribing to the standard strategy targeting levels of 7.0–7.9%.⁸ Indeed, the ADA has stated in its Standards of Medical Care that intensive glucose control may not be warranted in certain populations of patients with type 2 diabetes, such as those with a history of severe hypoglycemia, patients with limited life expectancy, children, patients with other comorbidities, and patients with long-standing diabetes and minimal or stable microvascular complications.² With continued disease progression, treatment will commonly advance to the maximum tolerable dose of the oral antidiabetic drug, then addition of a second or third drug. Ultimately, insulin remains the most effective antidiabetic medication for bringing glycemic levels closest to target; if disease progression continues, insulin therapy should be initiated or intensified.
However, the prevalence of type 2 diabetes and onset at increasingly younger ages have led to the consensus that treatment of this disease must take on a more aggressive approach. Indeed, other remedies have been proposed, such as initiating pharmacotherapy with oral antidiabetics in combination rather than as monotherapy,⁹ using oral drugs in combination with incretin mimetics,¹⁰ and initiating insulin therapy earlier.^5,6 Nevertheless, the progressive nature of type 2 diabetes means that advancement to insulin therapy is more often than not inevitable. The question then is which insulin regimen provides the most effective glycemic control. For patients in whom treatment with oral antihyperglycemic agents is inadequate, the current practice is to introduce a basal insulin. If subsequent insulin intensification is required, prandial insulin is added to the regimen.⁴ While basal–bolus therapy is the recommended regimen, another viable treatment option is the use of prandial pre-mixed therapy as an option for introducing prandial insulin in an insulin advancement strategy.^11,12

Options in Insulin Therapy
Regular and Intermediate-acting Insulin
The ideal insulin therapy will replicate the pattern of healthy pancreatic insulin secretion, cycling between the basal secretory levels of interprandial phases and the quick successive bursts observed in feeding. The problem with typical ‘regular’ human insulin, however, is that mealtime absorption is too slow and prandial glucose is not sufficiently controlled. With an onset of 30–60 minutes, it can be cumbersome for the patient to schedule doses 30 minutes prior to meals. Furthermore, the duration of regular insulin, spanning five to eight hours, can also pose a risk for hypoglycemia during post-prandial periods. The active duration and absorption and peak time of intermediate-acting basal insulin, neutral protamine Hagedorn (NPH) insulin, poses a similar risk.

Alternatively, insulin analogs are able to help correct the pharmacokinetic and pharmacodynamic limitations of the older regular and intermediate-acting insulins. Between the selection of rapid-acting (prandial), long-acting (basal), and pre-mixed (prandial plus basal), these insulin analogs can better mimic the physiological profile of insulin release over time (see Table 2).

Rapid-acting Insulin Analogs (Prandial/Bolus)
The rapid-acting insulin analogs—insulin aspart (Novolog®, Novo Nordisk), insulin glulisine (Apidra™, Sanofi-Aventis), and insulin lispro (Humalog®, Lilly)—are all similar in their activity, and are advantageous in that peak levels are higher and reached much closer to the time of injection compared with regular human insulin.^13,14 Furthermore, they also benefit from a shorter duration of action, which helps to reduce delayed hypoglycemia. These factors provide patients with increased dosing flexibility, allowing them to account for mealtime carbohydrate intake and plan for their insulin dosage accordingly and more accurately immediately prior to meals.

Long-acting Insulin Analogs (Basal)
Insulin detemir and insulin glargine have advantages over NPH: not only do these basal insulin analogs have prolonged duration of activity, they also lack the pronounced insulin peak seen in NPH,¹⁵ said to account for a decrease in the incidence of nocturnal and overall hypoglycemia. Oncedaily glargine has shown similar efficacy to NPH in improving glycemic control, although patients treated with glargine were able to reach their target without experiencing nocturnal hypoglycemia.¹⁶ Detemir twice daily was also comparable to NPH in terms of efficacy, with significantly less nocturnal hypoglycemia.¹⁷ The analogs have also shown lower interpatient variability in glucose levels compared with NPH and ultralente formulations,^18,19 suggesting that blood glucose readings may be more consistent over time in an individual. Insulin glargine has slightly higher intra-patient variability than NPH,²⁰ but less than ultralente.^21,22
Pre-mixed Insulin Analogs
The pre-mixed products are composed of various fixed-ratio mixtures, where a percentage of rapid-acting insulin is available for prandial phases, with the remainder of the mixture consisting of a protamine suspension of the insulin analog for basal periods. Insulin-naïve patients on oral antidiabetic drugs were randomized to receive either daily insulin glargine in combination with glimepiride and metformin or twice-daily 70% NPH/30% regular human insulin (70/30) without oral antidiabetic drugs; patients in the glargine subgroup experienced a more pronounced decrease in mean HbA_1c from baseline (-1.64 versus -1.31%; p<0.0003), and a greater proportion were able to reach a target HbA_1c level of ≤7.0% compared with the 70/30 cohort (31.6 versus 15.0%; p<0.0001).²³ In addition to greater efficacy, insulin glargine plus oral antidiabetic drugs were safer, with comparatively fewer mean hypoglycemic episodes per patient per year (4.07 versus 9.87; p<0.0001). This study suggests that there are several components that determine the results of these comparison studies, including the components forming the pre-mixed product, whether or not oral agents are continued, and the aggressiveness of the titration protocols. Other studies have shown an ability for twice-daily doses of biphasic insulin aspart 70/30 (NovoLog Mix 70/30, Novo Nordisk) or biphasic insulin lispro mix 75/25 (Humalog Mix 75/25™, Lilly) plus metformin to ameliorate glucose control and bring more patients to glycemic target compared with once-daily glargine plus metformin.^24–26 The nonrandomized and uncontrolled 1-2-3 Study treating 100 patients unable to reach their targets on oral medications with or without basal insulin showed that the addition of biphasic insulin aspart 70/30 to existing oral medications helped achieve glycemic targets through an incremental approach.²⁷ When biphasic insulin aspart 70/30 was used once daily, 41 and 21% of patients reached the ADA and AACE/IDF HbA_1c targets of <7.0 and <6.5%, respectively. Twice-daily use saw an increase to 70 and 52%, respectively, and in the proportion of patients requiring thrice-daily administration, 77 and 60% achieved the targets, respectively. Randomization of patients with type 2 diabetes with prior experience with oral antihyperglycemic drugs and insulin injections to receive either biphasic insulin lispro mix 50/50 (Humalog Mix 50/50™, Lilly) three times daily plus metformin or once-daily glargine plus metformin over a 24-week period showed significantly lower mean HbA_1c levels for the biphasic insulin lispro 50/50 group (7.1 [0.9] versus 7.5% [1.0%]; p<0.001), indicating improved glycemic control with pre-mixed insulin treatment.²⁸

Although these studies show an ability for pre-mixed insulin analogs to help patients achieve healthy HbA_1c targets, both the total daily insulin use and rate of hypoglycemic events are greater in patients using premixed insulins compared with patients using insulin glargine (see Table 3).
Basal–Bolus Therapy
Although the combination therapy of oral antidiabetic drugs and basal insulin can be quite successful in patients possessing sufficient endogenous insulin production to inhibit hepatic glucose production and reduce post-prandial glucose excursions, for many patients the disease will progress to the point at which pancreatic insulin secretion will become insufficient at controlling post-prandial glucose excursions; in these cases, a basal–bolus regimen must be initiated. This therapy, involving multiple daily injections, allows basal insulin to suppress gluconeogenesis between meals and overnight, while prandial (bolus) insulin increases post-prandial glucose levels. Basal–bolus therapy is the recommended approach for insulin intensification,⁴ as it provides a physiological approach to treating type 2 diabetes. Although it offers a more aggressive insulin regimen that allows for tighter control over glycemic levels for patients who cannot otherwise achieve glycemic control with oral antidiabetic drugs and other insulin-based therapies, basal–bolus therapy is commonly perceived as being too complex. If patients believe the regimen to be too difficult or time-consuming to implement, adherence is likely to be low, leading to treatment failure.

Basal–bolus strategies can be simplified, however. A study by Bergenstal et al. randomized insulin-experienced patients to one of two groups in which they were taught to employ different algorithms in adjusting their insulin doses.²⁹ Both groups used the same algorithm for the adjustment of basal insulin glargine: initial insulin dose was calculated as 50% of the total daily dose prior to randomization, with subsequent doses titrated weekly according to the mean fasting self-monitored blood glucose (SMBG) from the previous three days. The remaining 50% of the total daily insulin dose was used for bolus insulin, and split three ways to cover meals: 50% for the largest meal containing the most carbohydrates, 33% for the mid-sized meal, and 17% for the smallest. Both groups adjusted their bolus insulin dose based on mealtime blood glucose patterns from the previous week. In one group, patients simply adjusted their insulin units depending on the mealtime dose and the blood glucose values of the previous week. In the other group, patients were taught to count carbohydrates and to use an insulin-to-carbohydrate ratio to adjust their insulin based on the carbohydrates to be eaten at each meal (see Table 4). After 24 weeks, the percentage of patients in these two treatment algorithms achieving HbA_1c <7.0% were 73.0 and 69.2%, respectively (p=0.70). The demonstrated effectiveness of these two options in managing mealtime insulin doses may therefore increase the willingness of patients and clinicians alike to undertake basal–bolus insulin therapy in order to achieve optimal glucose control. Basal–Bolus versus Prandial Pre-mixed Therapy
Two recent clinical trials have assessed different insulin regimens, and early data from these trials have provided important information with implications for clinical practice. Holman and colleagues recently reported one-year data from the Treating to Target in Type 2 Diabetes (4-T) study on the addition of three insulin regimens to oral therapy in patients with type 2 diabetes who have suboptimal glycemic control on oral agents.¹¹ Rosenstock et al. recently published 24-week data from a trial evaluating basal–bolus versus prandial pre-mixed therapy in patients with type 2 diabetes who had previously failed to achieve glycemic targets under the combined therapy of insulin glargine and oral antihyperglcyemic drugs.¹²

The ongoing 4-T study is a three-year open-label, randomized, controlled study evaluating biphasic insulin twice daily (biphasic insulin aspart 70/30), prandial insulin three times daily (insulin aspart), or basal insulin once daily (insulin detemir) in 708 patients with type 2 diabetes and inadequate glucose control (HbA_1c 7.0–10%) despite taking maximally tolerated doses of metformin and sulfonylurea. The patients in the study continued their usual doses of metformin and sulfonylurea in addition to the insulin regimens. At one year, mean HbA_1c was similar between the biphasic and prandial group at 7.3 and 7.2%, respectively (p=0.08), with a higher mean HbA_1c of 7.6% in the basal group (p<0.001 for basal versus biphasic or prandial). Each analog insulin regimen produced a sustained decrease in HbA,sub>1c at one year (-1.3% with biphasic, -1.4% with prandial, and -0.8% with basal insulin). Target HbA_1c values ≤7.0% differed significantly between the basal groups and the other two groups: only 27.8% of patients in the basal group reached this target compared with 41.7 and 48.7% of the biphasic and prandial groups, respectively (p<0.001 for both comparisons with basal). Although the biphasic and prandial insulin regimens produced relatively lower mean HbA_1c levels compared with the basal regimen, the basal regimen was associated with fewer hypoglycemic events (2.3 mean hypoglycemic episodes per patient per year versus 5.7 and 12 for biphasic and prandial insulin, respectively). Furthermore, the biphasic and prandial regimens were associated with greater weight gain (mean weight gain 4.7, 5.7, and 1.9kg, respectively).
In the first ever head-to-head comparison of prandial pre-mixed therapy and basal–bolus therapy, 374 patients with type 2 diabetes who had previously failed to achieve glycemic targets under the combination therapy of insulin glargine and oral antihyperglycemic drugs were randomized to receive either biphasic insulin lispro mix 50/50 three times daily with meals plus oral agents or insulin glargine plus mealtime insulin lispro plus oral agents.¹² The primary outcome of efficacy measured the change in HbA_1c levels from baseline to study end-point for each treatment group; although baseline HbA_1c levels were similar in the two groups, pre-mixed therapy saw a reduction of 1.87%, whereas patients undergoing basal–bolus treatment experienced a reduction of 2.09% (p=0.021)—a difference of -0.22% between the treatment arms. The hypothesis that the pre-mixed therapy was non-inferior to basal–bolus therapy in terms of glycemic control could therefore not be demonstrated, even based on the pre-defined non-inferiority margin of 0.3%. All patients had similar total daily glargine doses at study entry, but at 24 weeks the mean total daily insulin dose was significantly greater for the basal–bolus arm (14±85 units [1.4±0.8 units/kg]) than the pre-mixed insulin group (123±69 units [1.2±0.5 units/kg]; p=0.002). Weight gain and incidence of hypoglycemic events were similar between the two groups. Although this study was unable to demonstrate noninferiority, with basal–bolus therapy exhibiting a trend toward greater reductions in HbA1c levels from baseline, both basal–bolus and pre-mixed insulin treatments in conjunction with oral antihyperglycemic agents proved effective in lowering HbA_1c levels in patients with type 2 diabetes who were previously unresponsive to treatment with insulin glargine and oral drugs.

Conclusion
With the increasing incidence of type 2 diabetes among the general population and its associated micro- and macrovascular complications, it is only sensible to further develop more effective and aggressive strategies for treating type 2 diabetes. The proven efficacy in improving glycemic control through the insulin analogs and pre-mixed insulin analogs is only one aspect of these advances; novel treatment regimens and algorithms are also available to help assist patients with insulin therapy. It should be stressed that pharmacological therapy alone is not enough to guarantee amelioration of patient condition; controlling diabetes requires frequent monitoring on the patient’s part, and for this reason patient education and participation are vital to achieving euglycemia. Patient adherence is always a large deciding factor in the success of any treatment for diabetes, and even more so in complex insulin regimens such as basal–bolus therapy, which may arguably be at the forefront of currently available antidiabetic regimens. The use of pre-mixed insulins can also be effective in terms of HbA_1c reduction, reduced hypoglycemia, and number and simplicity of daily injections. The choice of any regimen truly depends to a large degree on whether the patient can conform to the complexity of the regimen over the long term.■