Basal Insulin Preparations Research Articles

Evaluating Patient and Provider Preferences for a Once-Weekly Basal Insulin in Adults with Type 2 Diabetes.

The global burden of disease of type 2 diabetes (T2D) is significant, and insulin currently plays a central role in T2D management. This study sought to assess the preferences of patients with T2D and healthcare providers (HCPs) involved in T2D care regarding a hypothetical once-weekly basal insulin in comparison to current basal insulin options. In a survey-based study in the United States that included a discrete choice experiment (DCE), patients with T2D (insulin naïve and current insulin users) and providers who treat individuals with T2D were asked to evaluate current basal insulins and identify attributes of importance regarding a hypothetical once-weekly basal insulin. A regression analysis was conducted to identify drivers of preference by relevant demographics, attitudes, and behaviors. Most respondents (91% of patients with T2D and 89% of HCPs in the base case scenario) would choose a once-weekly basal insulin product over another type of basal insulin. Both patients with T2D and HCPs rated insulin type and delivery method to be attributes of highest importance in the discrete choice exercise. Current basal insulin users ("insulin experienced") reported higher levels of confidence that a once-weekly insulin would help them to achieve their desired blood sugar levels compared to their current basal insulin (5.7 vs 5.2 on a 7-point Likert scale). Most insulin-experienced respondents (88%) were likely to inquire about once-weekly basal insulin, and most HCPs (85%) indicated willingness to educate patients on management of their T2D using a once-weekly basal insulin. Discussing preferences for T2D medication management is important for patients and HCPs to ensure treatments are offered for patients based on their preferences. This study showed that patient and provider preferences are similar towards a once-weekly basal insulin over current basal insulin preparations.

Weekly Insulin Becoming a Reality

Insulin was first isolated in 1921 and developed as a therapeutic agent in the 1920s. The initial crude preparations were injected multiple times daily because of their short duration of action. Consequently, there were many attempts to develop insulin preparations with prolonged biological availability in the hope that less frequent once-daily administration would be feasible (1). A host of such preparations were introduced, including protamine insulin, protamine zinc insulin, surfen insulin, globin insulin, iso-insulin, isophane insulin (NPH), and insulin zinc suspensions (lente insulins) (1) (Fig. 1). The goal was mainly to reduce the number of injections and thus the patient burden. Yet, with the development of a radioimmunoassay for insulin (2), it became apparent that physiologic insulin secretion involved two components: meal-related insulin secretion with postprandial spikes and basal insulin secretion that remains relatively constant with some minor pulsatility (3). Subsequently, as modern insulin therapy evolved, facilitated by patient self-monitoring of blood glucose (4,5), it became apparent that the inherent peaks in basal insulin preparations, such as with the nonsoluble NPH or lente insulins, created risk of hypoglycemia, especially if the insulin vials were not correctly rolled to create a proper suspension. Moreover, these insulins did not have sufficiently long duration of action to be used once daily. Consequently, in addition to making them soluble, two of the goals in development of basal insulin analogs, such as insulin glargine and insulin detemir, were to eliminate insulin peaks and to prolong the action to approach 24 h (6,7). Second-generation basal insulin analogs, such as insulin degludec and insulin glargine U300, came with …

Basal insulin treatment optimization in T2DM: GLP-1 Receptor Agonists in loose addition or in fixed dose combination

Administration of basal insulin formulations is often used when oral therapies fail to achieve and/or maintain adequate glucose control in T2DM. However, observational studies documented that a large percentage of basal insulin treated subjects fails to achieve glycemic targets. Among the possible strategies to intensify basal insulin therapy, addition of a GLP-1 RA has several advantages. Indeed GLP-1 RA mechanism of action could be seen as complementary to insulin action. Furthermore, studies have shown that addition of a GLP-1 RA to basal insulin improves HbA1c with a minimal increase in the risk of hypoglycemia and null or modest weight gain. Addition of a GLP-1 RA to basal insulin therapy might be easier if performed by switching from daily basal insulin injections to daily injections of a fixed dose combination of a GLP-1 RA+basal insulin preparation. Two such fixed combinations are presently available, IDegLira (Degludec Insulin + Liraglutide) and IGlarLixi (Insulin Glargine+Lixisenatide). Two studies with IDegLira and one study with IGlarLixi have shown that these combinations are more efficacious and safer than mere up-titration of basal insulin. Use of fixed dose GLP-1 RA+basal insulin combination appears therefore an excellent strategy of basal insulin intensification. No studies are availbe directly comparing efficacy and safety of IGlarLixi and IDegLira. Data obtained in registration trials appear numerically better for IDegLira. Furthermore, as compared to IGlarLixi, IDegLira offers a greater flexibility in time of administration. KEY WORDS basal insulin; GLP-1 RA; liraglutide; lixisenatide; fixed dose combination.

Challenges of Diabetes Care in Older People With Type 2 Diabetes and the Role of Basal Insulin.

IN BRIEF The use of long-acting basal insulin analogs is a recommended strategy in older people with diabetes because of their lower risk of hypoglycemia compared to intermediate-acting insulins. In this article, we review the results from recent clinical trials of second-generation basal insulin preparations. We conclude that, although these preparations have improved the management of insulin-requiring older people with type 2 diabetes, there is a need for additional and more specific studies to address the complexities of hyperglycemia management in this population.

Differentiating Basal Insulin Preparations: Understanding How They Work Explains Why They Are Different.

Since the introduction of insulin as a life-saving agent for patients with type 1 diabetes, insulin preparations have evolved to approximate physiologic insulin delivery profiles to meet prandial and basal insulin needs. While prandial insulins are designed to have quick time–action profiles that minimize postprandial glucose excursions, basal insulins are designed to have a protracted time–action profile to facilitate basal glucose control over 24 h. Given that all insulins have the same mechanism of action at the target tissue level, the differences in time–action profiles are achieved through different mechanisms of protraction, resulting in different behaviors in the subcutaneous space and different rates of absorption into the circulation. Herein, we evaluate the differences in basal insulin preparations based on their differential mechanisms of protraction, and the resulting clinical action profiles. Multiple randomized control trials and real-world evidence studies have demonstrated that the newer second-generation basal insulin analogs, insulin glargine 300 units/mL and insulin degludec 100 or 200 units/mL, provide stable glycemic control with once-daily dosing and are associated with a reduced risk of hypoglycemia compared with previous-generation basal insulin analogs insulin glargine 100 units/mL and insulin detemir. These advantages can lead to decreased healthcare resource utilization and cost. With this collective knowledge, healthcare providers and payers can make educated and well-informed decisions when determining which treatment regimen best meets the needs of each individual patient.Funding: Sanofi US, Inc.

A comparison of the clinical courses of type 2 diabetic patients whose basal insulin preparation was replaced from insulin glargine 100 units/mL to insulin glargine biosimilar or 300 units/mL: a propensity score-matched observation study

Objective: We compared the clinical course of type 2 diabetic patients whose basal insulin preparations were replaced from insulin glargine (IGlar) 100 units/mL (U100) to IGlar biosimilar or IGlar 300 units/mL (U300).Methods: After propensity score matching, 34 patients whose basal insulin preparation was switched from IGlar U100 to IGlar biosimilar and 102 switched to IGlar U300 were observed for 6 months.Results: The HbA1c level and body weight did not change significantly after the replacement in the IGlar biosimilar or IGlar U300 groups. In the IGlar biosimilar group, the frequency of subjects who experienced hypoglycemia after the replacement (12%) was not different from before (12%). However, the frequency was significantly lower after the replacement (2%) than before (13%) in the IGlar U300 group. The change in the HbA1c level after the replacement showed a significant association with the HbA1c level at the baseline but not with the kind of IGlar. Hypoglycemia was frequently observed in subjects who had experienced hypoglycemia before the replacement.Conclusions: IGlar biosimilar and IGlar U300 induced similar HbA1c and body weight changes among type 2 diabetic patients. IGlar biosimilar is a suitable option for patients with a low risk for hypoglycemia.

Systematic review and meta-analysis of randomized clinical trials comparing efficacy and safety outcomes of insulin glargine with NPH insulin, premixed insulin preparations or with insulin detemir in type 2 diabetes mellitus.

AimsA variety of basal insulin preparations are used to treat patients with type 2 diabetes mellitus (T2DM). We aimed to summarize scientific evidence on relative efficacy and safety of insulin glargine (IGlar) and other insulins in T2DM.MethodsA systematic review was carried out in major medical databases up to December 2012. Relevant studies compared efficacy and safety of IGlar, added to oral drugs (OAD) or/and in combination with bolus insulin, with protamine insulin (NPH) or premixed insulin (MIX) in the same regimen, as well as with insulin detemir (IDet), in T2DM. Target HbA1c level without hypoglycemic events was considered the primary endpoint.ResultsTwenty eight RCTs involving 12,669 T2DM patients followed for 12–52 weeks were included in quantitative analysis. IGlar + OAD use was associated with higher probability of reaching target HbA1c level without hypoglycemia as compared to NPH + OAD (RR = 1.32 [1.09, 1.59]) or MIX without OAD (RR = 1.61 [1.22, 2.13]) and similar effect as IDet + OAD (RR = 1.07 [0.87, 1.33]) and MIX + OAD (RR = 1.09 [0.86, 1.38]). IGlar + OAD demonstrated significantly lower risk of symptomatic hypoglycemia as compared to NPH + OAD (RR = 0.89 [0.83, 0.96]), MIX + OAD (RR = 0.75 [0.68, 0.83]) and MIX without OAD(RR = 0.75 [0.68, 0.83]), but not with IDet + OAD (RR = 0.99 [0.90, 1.08]). In basal-bolus regimens, IGlar demonstrated similar proportion of T2DM patients achieving target HbA1c as compared to NPH (RR = 1.14 [0.91, 1.44]) but higher than MIX (RR = 1.26 [1.12, 1.42) or IDet (RR = 1.38 [1.11, 1.72]). The risk of severe hypoglycemia was lower in IGlar than in NPH (RR = 0.77 [0.63, 0.94]), with no differences in comparison with MIX (RR = 0.74 [0.46, 1.20]) and IDet (RR = 1.10 [0.54, 2.25]). IGlar + OAD has comparable safety profile to NPH, with less frequent adverse events leading to treatment discontinuation than MIX + OAD (RR = 0.41 [0.22, 0.76]) and IDet + OAD (RR = 0.40 [0.24, 0.69]). Also severe adverse reactions were less common for IGlar + OAD when compared to MIX + OAD (RR = 0.71 [0.52; 0.98]).ConclusionFor the majority of examined efficacy and safety outcomes, IGlar use in T2DM patients was superior or non-inferior to the alternative insulin treatment options.Electronic supplementary materialThe online version of this article (doi:10.1007/s00592-014-0698-4) contains supplementary material, which is available to authorized users.

Patient safety and minimizing risk with insulin administration - role of insulin degludec.

Diabetes is a lifelong condition requiring ongoing medical care and patient self-management. Exogenous insulin therapy is essential in type 1 diabetes and becomes a necessity in patients with longstanding type 2 diabetes who fail to achieve optimal control with lifestyle modification, oral agents, and glucagon-like peptide 1-based therapy. One of the risks that hinders insulin use is hypoglycemia. Optimal insulin therapy should therefore minimize the risk of hypoglycemia while improving glycemic control. Insulin degludec (IDeg) is a novel basal insulin that, following subcutaneous injection, assembles into a depot of soluble multihexamer chains. These subsequently release IDeg monomers that are absorbed at a slow and steady rate into the circulation, with the terminal half-life of IDeg being ~25 hours. Thus, it requires only once-daily dosing unlike other basal insulin preparations that often require twice-daily dosing. Despite its long half-life, once-daily IDeg does not cause accumulation of insulin in the circulation after reaching steady state. IDeg once a day will produce a steady-state profile with a lower peak:trough ratio than other basal insulins. In clinical trials, this profile translates into a lower frequency of nocturnal hypoglycemia compared with insulin glargine, as well as an ability to allow some flexibility in dose timing without compromising efficacy and safety. Indeed, a study that tested the extremes of dosing intervals of 8 and 40 hours showed no detriment in either glycemic control or hypoglycemic frequency versus insulin glargine given at the same time each day. While extreme flexibility in dose timing is not recommended, these findings are reassuring. This may be particularly beneficial to elderly patients, patients with learning difficulties, or others who have to rely on health-care professionals for their daily insulin injections. Further studies are required to confirm whether this might benefit adherence to treatment, reduce long-term hypoglycemia or reduce diabetes-related complications.

Insulin therapy for type 2 diabetes

Insulin therapy provides effective glycemic control in patients with diabetes who have deficient beta-cell function and insulin secretion. Subjects with type 2 diabetes not adequately controlled on oral agents or incretin therapies can initiate basal insulin replacement to correct fasting hyperglycemia. While all basal insulin preparations have similar efficacy in lowering fasting plasma glucose and improving A1C, the newer basal insulin analogs are associated with a lower risk of hypoglycemia than NPH insulin. Patients whose A1C levels remain above goal despite adequate basal insulin replacement need to evaluate and correct post-prandial hyperglycemia. With progressive beta-cell deficiency, rapid-acting insulin preparations can be introduced before one or more meals and titrated to achieve post-prandial glycemic control. For many patients requiring full basal/bolus insulin replacement, a strategy of fixed prandial insulin doses can yield acceptable glycemic control when compared to a more sophisticated approach utilizing carbohydrate counting and matching to insulin. Concentrated insulin preparations such as U-500 have also been of value in patients with resistant type 2 diabetes. Regardless of the type of insulin replacement used, the blood glucose lowering effects of insulin need to be carefully balanced with the increasing risk of hypoglycemia, and the weight gain associated with insulin intensification.

Similarity of pharmacodynamic effects of a single injection of insulin glargine, insulin detemir and NPH insulin on glucose metabolism assessed by 24‐h euglycaemic clamp studies in healthy humans

Two long-acting insulin analogues, insulin glargine and insulin detemir, have been developed as alternatives to neutral protamine Hagedorn (NPH) insulin, which has been the preferred basal insulin preparation for decades. The aim was to directly compare the pharmacodynamic properties of the long-acting insulin analogues and NPH insulin after a single subcutaneous injection. The study was conducted as a double-blind, controlled, three-arm, crossover study including 10 healthy lean male volunteers. On three different occasions, each subject was challenged with 0.4 U kg(-1) of either insulin glargine, insulin detemir or NPH insulin. Plasma glucose was maintained at 0.3 mmol l(-1) below fasting level by glucose clamping for 24 h. C-peptide, insulin, free fatty acids (FFAs) and counter regulatory hormones were measured throughout the clamp period, whereas endogenous glucose release (EGR) was assessed by isotope dilution technique (3-(3)H-glucose). The mean glucose infusion rate (GIR)-time profiles revealed no significant differences between the three preparations in the primary endpoints: Maximal GIR of approximately 3.4 mg kg(-1) min(-1) (P = 0.68), time to maximal GIR of approximately 10 h (TR(max)) (P = 0.35) and area under the GIR curve (GIR(AUC)) (P = 0.81). Compared with the other insulin preparations, EGR (see above)was lower for insulin detemir at the beginning of the clamp period (330-360 min) (P = 0.007) while GIR was lower (P = 0.005) and FFA concentrations were higher (P = 0.005) during the last 4 h of the clamp. In this experimental design, only minor pharmacodynamic differences were demonstrated between insulin detemir, insulin glargine and NPH insulin.

Insulin treatment of Type 2 diabetes: a clinical perspective

Some copies of this issue of the Journal of Diabetes are being distributed in China with a reprint describing the findings of a consensus conference organized by NovoNordisk on how best to use the combination of 30% insulin aspart (rapid-acting) and 70% protamine-based (intermediate-acting) insulin (BIAsp 30).1 The article offers guidance in approaches to intensifying treatment with this form of insulin, but does not compare BIAsp 30 with other insulin treatment regimens, particularly for people with Type 2 diabetes, a most interesting and important topic. It is not widely appreciated that the UK Prospective Diabetes Study (UKPDS) presented evidence that Type 2 diabetic people receiving either of the sulfonylureas (SU) used for initial treatment had progressively increasing need for addition of insulin over time, with nearly 10% needing this treatment after 1 year, and a linear increase to approximately half requiring this by 6 years.2 Insulin alone was inferior to combined treatment with insulin + SU in maintaining glycemic control.2 Although one may argue that in the current era of the availability of multiple oral agents the use of insulin is less necessary, comparison of maximal dose metformin and pioglitazone plus titrated SU treatment versus metformin plus BIAsp 30 showed that although either approach could successfully maintain excellent glycemic control, the former led to both a greater increase in weight and an increasing frequency of hypoglycemia.3 Therefore, insulin plus oral agents may be a preferable approach to thiazolidinedione/SU/metformin combinations for many Type 2 diabetic people. Multiple approaches have been shown to be effective with insulin treatment. The rapid-acting insulin analogs lispro, aspart, and glulisine lead to more physiologic replication of the normal postprandial insulin secretory pattern,4 with a reduction in postprandial glycemia.5-7 The use of such analogs in combination with a protamine-containing intermediate-acting insulins led to the development of BIAsp 30 and to the similar Eli Lilly product, namely protamine-lispro 75%/lispro 25% (BI-lispro 25), both of which have the advantage over both intermediate-acting insulin alone and combinations of regular human insulin plus intermediate-acting insulin of better reducing postprandial glycemia8, 9 while maintaining benefit in overnight glucose-lowering.10 Furthermore, these preparations have greater simplicity of administration, with the potential for a reduced number of injections. However, one problem with all such protamine-containing insulin preparations is their pronounced peak effect, often occurring at an undesirable time after evening administration,11 so that although effective in improving glycemia, many studies suggest that they do so at the expense of a greater likelihood of nocturnal hypoglycemia than seen with the ‘peakless’ insulin analogs detemir and glargine.12 (It should be noted that not all authors have reported this finding.13) Furthermore, intermediate-acting insulin given alone may not be quite as effective as insulin glargine in lowering A1c.14 Detemir appears to have less variability in overnight glucose-lowering action than seen either with protamine–intermediate-acting insulin or with insulin glargine,15 with studies comparing it with intermediate-acting insulin showing lesser degrees of weight gain.16 The question should then be asked, which is better: basal insulins, such as protamine-containing preparations, glargine, or detemir; bolus insulins, particularly the rapid-acting analogs lispro, aspart, and glulisine; or the combination insulin preparations BIAsp 30 and BI-lispro 25? This question was addressed by the Treating to Target in Type 2 Diabetes (4-T) study.17 A total of 708 Type 2 diabetic people were randomized to BIAsp 30, to aspart three times daily before meals, or to insulin detemir once or twice daily. At 1 year, the detemir group had a lesser improvement in A1c but less weight gain, less hypoglycemia, and a lower total daily insulin dose. After 3 years, when all patients were moved to a multiple daily insulin (MDI) approach, hypoglycemia rates remained significantly lower in those started on insulin detemir and, in addition, these patients continued to exhibit less weight gain even though the glycemic improvement was now similar across all groups. Furthermore, cardiovascular mortality was significantly lower in the group started on basal insulin initially and significantly more serious adverse events occurred in those people initially randomized to BIAsp 30.18 This context should be used in interpreting the consensus statement of Unnikrishnan et al.1 regarding intensification of insulin therapy with BIAsp 30. The authors appropriately suggest that this preparation, dosed up to three-times daily, may allow improved glycemic control over basal insulin preparations and present evidence supporting this concept. Although requiring considerable effort on the parts of both the clinician and the diabetic patient, initial use of basal insulin titrated to complex basal-bolus MDI regimens may be preferable to multiple doses of either BIAsp 30 or BI-Lispro 25, so that one should strongly consider MDI as the optimal treatment for management of insulin-requiring patients with Type 2 or Type 1 diabetes.

Beyond the Era of NPH Insulin—Long-Acting Insulin Analogs: Chemistry, Comparative Pharmacology, and Clinical Application

The new rDNA and DNA-derived "basal" insulin analogs, glargine and detemir, represent significant advancement in the treatment of diabetes compared with conventional NPH insulin. This review describes blood glucose homeostasis by insulin in people without diabetes and outlines the physiological application of exogenous insulin in patients with type 1 and type 2 diabetes. The requirements for optimal basal insulin treatment are discussed and the methods used in the evaluation of basal insulins are presented. An essential criterion in the development of an "ideal" basal insulin preparation is that the molecular modifications made to the human insulin molecule do not compromise safety. It is also necessary to obtain a clear understanding of the pharmacokinetic and pharmacodynamic characteristics of the two currently available basal insulin analogs. When comparing glargine and detemir, the different molar concentration ratios of the two insulin formulations should be considered along with the nonspecificity of assay systems used to determine insulin concentrations. However, euglycemic clamp studies in crossover study design provide a good basis for comparing the pharmacodynamic responses. When the latter is analyzed by results of intervention clinical trials, it is concluded that both glargine and detemir are superior to NPH in type 1 and type 2 diabetes. However, there is sufficient evidence to demonstrate that these two long-acting insulin analogs are different in both their pharmacokinetic and pharmacodynamic profiles. These differences should be taken into consideration when the individual analogs are introduced to provide basal insulin supplementation to optimize blood glucose control in patients with type 1 and type 2 diabetes as well. PubMed-Medline was searched for articles relating to pharmacokinetics and pharmacodynamics of glargine and detemir. Articles retrieved were reviewed and selected for inclusion if (1) the euglycemic clamp method was used with a duration >or=24 h, (2) a single subcutaneous dose of glargine/detemir was used, and (3) area under the curve for insulin concentrations or glucose infusion rates were calculated.

Insulin detemir is characterized by a more reproducible pharmacokinetic profile than insulin glargine in children and adolescents with type 1 diabetes: results from a randomized, double-blind, controlled trial*

Insulin detemir (detemir) has previously been shown to be associated with lower within-subject variability compared with other basal insulin preparations in adults with type 1 diabetes mellitus (T1DM). This randomized, double-blind, crossover trial compared the within-subject variability of detemir and insulin glargine (glargine) in pharmacokinetic properties in children and adolescents with T1DM. The trial enrolled 32 children and adolescents (19 girls and 13 boys; mean +/- SD: age 13 +/- 2.5 yr and T1DM duration 6.3 +/- 3.0 yr) with a hemoglobin A1c (HbA1c) of 7.9 +/- 1.0%. Participants were randomized to a specific treatment sequence in which a dose of 0.4 U/kg of detemir and glargine was injected subcutaneously 24 h apart at each of two dosing visits. Insulin concentrations were measured at frequent intervals for a period of 16-h post-dosing. Detemir showed statistically significantly less within-subject variability compared with glargine with a 3.1-fold and 2.9-fold lower coefficient of variation (CV, %) for the area under the concentration-time curve [AUC((0-16) (h))] and the maximum concentration (C(max)), respectively. Separate analyses demonstrated a 2.5-fold and 2.9-fold lower CV (%) with detemir in children (8-12 yr) and a 4-fold and 3.8-fold lower CV (%) with detemir in adolescents (13-17 yr). No safety concerns were raised during the trial. In conclusion, within-subject variability in pharmacokinetic properties was significantly lower for detemir than for glargine in children and adolescents with T1DM. This indicates a less variable absorption with detemir, which is expected to be associated with a more predictable therapeutic effect also in this population.

Comparison of Pharmacokinetics and Dynamics of the Long-Acting Insulin Analogs Glargine and Detemir at Steady State in Type 1 Diabetes: a Double-Blind, Randomized, Crossover Study

We thank Dr. Banarer (1) for his appreciation of our work (2) and for the opportunity to discuss his criticism. The formula we used to describe the insulin activity profile was constructed to emphasize the ability of a basal insulin preparation to maintain plasma glucose at the target value during fasting, which is the clinical target of a basal insulin preparation. Accordingly, the second variable of the formula, plasma glucose concentration, was given greater power. The impact …

Insulin detemir: A review

Patients with diabetes are at increased risk of mortality and morbidity from micro- and macrovascular complications (1, 2). Landmark studies in type 1 and 2 diabetes have clearly shown that improved glycemic control leads to better outcomes (3-6). With the introduction of the General Medical Service contract, the England and Wales National Service Framework, and other schemes, there is a national drive to improve control in patients with diabetes. The treatment of diabetes was revolutionized shortly after the turn of the 20th century by the extraction and purification of insulin. Since methods to protract (i.e., prolong) the action of insulin were developed in the 1930s, little changed in this technology until the turn of this century. At this time there was renewed interest in the importance of basal insulin in controlling diabetes and thus preventing or delaying complications, and so technology advanced again. Two new basal insulin analogues have come to the market: insulin glargine, which has been widely used for some years now, and detemir. This review describes the novel method of protraction employed by insulin detemir, discusses the possible therapeutic benefits of this method of protraction, and describes the findings of studies comparing insulin detemir with other currently available basal insulin preparations. It is not the intention of this paper to be a review of all the currently available long-acting insulin analogues.

Are our insulins more or less predictable than our patients?

AbstractPatients with insulin‐treated diabetes often report day‐to‐day variability in blood glucose levels. Suboptimal patient self‐management may often be considered the most likely cause, but studies have not consistently demonstrated a relationship between adherence and control. Patient behaviours such as insulin resuspension and dose setting technique will contribute to erratic glycaemic control, but because many patients who appear to adhere faithfully to their insulin regimens still report erratic, unpredictable blood glucose, it seems likely that limitations in the prescribed therapy itself might be at least partly causal. Indeed, studies investigating repeat doses of exogenous insulins have shown that the pharmacokinetic and pharmacodynamic profiles that follow each individual insulin injection can vary considerably from the overall mean profiles, both within and between patients. For traditional basal insulin preparations (such as NPH), this variability, combined with a peak in absorption, may contribute to nocturnal hypoglycaemia, which will limit the attainment of glycaemic targets. Recent biotechnological advances have, however, allowed insulin analogues with modified pharmacokinetic properties to be designed with the intent of improving post‐prandial or basal glycaemic control. For example, two analogue preparations (insulin glargine and insulin detemir) have recently been marketed and offer a protracted profile of action that is well suited to basal insulin substitution. Insulin detemir, for example, has been shown to offer greater within‐person predictability in duration of action and maximal effect than other basal insulins. Such improvements offer the potential to provide better and more predictable glucose control through modification of the insulin regimen as well as through the encouragement of improved patient self‐management techniques. Copyright © 2004 John Wiley & Sons, Ltd.

The 12-Month Efficacy and Safety of Insulin Detemir and NPH Insulin in Basal-Bolus Therapy for the Treatment of Type 1 Diabetes

This trial compared the long-term safety and efficacy of the basal insulin preparations, insulin detemir and NPH insulin, in basal-bolus therapy for patients with type 1 diabetes. This multinational open, parallel-group trial randomized patients to receive insulin detemir or NPH insulin twice daily in addition to mealtime human soluble insulin. Doses were titrated towards predefined glycemic targets. After an initial 6-month treatment period, patients were invited to participate in a 6-month extension period. A total of 289 from 421 elected to continue in the trial, of which 252 completed. Glycemic control as assessed by hemoglobin A1c (insulin detemir, 7.88%; NPH insulin, 7.78%; difference not significant) and fasting plasma glucose (insulin detemir, 10.1 mmol/L; NPH insulin, 9.84 mmol/L; difference not significant) was similar in both treatment groups at end point, with hemoglobin A1c little changed from baseline and fasting plasma glucose slightly decreased. There was some evidence for a risk reduction for hypoglycemia in association with insulin detemir, although this was not statistically significant (relative risk overall hypoglycemia, 0.71, P = 0.139; relative risk nocturnal hypoglycemia, 0.71, P = 0.067), and hypoglycemic events were fewer in each of the 12 months. There was a significant treatment difference with regard to weight outcome; NPH insulin was associated with weight gain (1.4 kg), but there was no mean weight gain (-0.3 kg) in the insulin detemir cohort (baseline-adjusted between-group difference at 12 months, 1.66 kg, P = 0.002). There were no obvious between-group differences in other safety parameters. Glycemic control is maintained with insulin detemir during long-term treatment. At equivalent glycemic control to NPH insulin, insulin detemir is associated with a lack of weight gain and a trend towards a reduced risk of nocturnal hypoglycemia when used in basal-bolus therapy with mealtime soluble human insulin.

Insulin detemir: improving the predictability of glycaemic control.

The importance of strict glycaemic control in reducing diabetes-related outcomes is well recognised. Yet, despite the range of available treatment options, clinical experience suggests that individuals with diabetes frequently fail to achieve good glucose control. Instead, patients often have poorly controlled, unpredictable blood glucose levels. In insulin-treated patients, one of the reasons for this may be the inherently variable action of exogenously injected insulin. For example, the currently available longer-lasting insulin preparations that aim to provide a continuous basal level of circulating insulin are associated with markedly variable action both between and within subjects. Unpredictable insulin action contributes to variable blood glucose control, which in addition to increasing the risk of hypoglycaemia has also been shown to be an independent risk factor for mortality. It is hoped that advances in longer-lasting insulin preparations will provide significant benefits to patients, improving control and reducing variability. A new, long-lasting analogue, insulin detemir, has been shown to be significantly less variable than other basal insulin preparations in pharmacological and clinical studies. The improved predictability in insulin response offered by insulin detemir may be associated with a number of clinical benefits including a reduction in hypoglycaemia and weight gain.

Insulin glargine

Background: In diabetes mellitus, the clinical goal of intensive glycemic control (lowering blood glucose concentrations to normal or near-normal levels) has been hindered by the lack of insulin regimens that duplicate the basal-bolus secretion of insulin by the healthy pancreas. In particular, intensive therapy has been associated with a risk of hypoglycemia. Objective: This article reviews the pharmacology, pharmacokinetics, dosing guidelines, adverse effects, and potential drug interactions of insulin glargine, a new long-acting recombinant human insulin analogue. Results of clinical trials of its efficacy and tolerability as a basal insulin in the treatment of type 1 and type 2 diabetes are summarized. Methods: Primary research and review articles on insulin glargine were identified through a search of MEDLINE from 1966 to July 2001. Abstracts were identified through a search of the Institute for Scientific Information Web of Science from 1995 to July 2001 and proceedings of American Diabetes Association scientific meetings. Additional information was obtained from the product information for insulin glargine. All identified articles and abstracts were evaluated for relevance, and all relevant information was included in the review. Priority was given to data from the primary medical literature. Results: Insulin glargine has a slower onset of action than human neutral protamine Hagedorn (NPH) insulin, a longer duration of action (up to 24 hours), and no pronounced peak. It has similar tolerability and produces similar glycemic control to once- or twice-daily human NPH insulin, with a similar glucose-lowering effect on a molar basis. A decreased incidence of hypoglycemia, particularly at night, has been reported with insulin glargine compared with human NPH insulin. Insulin glargine appears to be comparable to human NPH insulin in terms of toxicity, adverse effects, immunogenicity, and potential for drug interactions. Results of clinical trials of insulin glargine in both type 1 and type 2 diabetes support its use in combination with a short-acting insulin, insulin lispro, or oral antidiabetic medications. Although insulin glargine cannot be mixed with other insulin preparations, it has the potential convenience of providing basal insulin with once-daily bedtime dosing. Conclusions: Based on the as yet small amount of data from full clinical study reports in peer-reviewed publications, insulin glargine appears to be a well-tolerated and effective basal insulin preparation for patients with type 1 or type 2 diabetes (including pediatric patients). Its delayed onset of action and prolonged, flat time—action profile mimic the action of endogenous basal insulin (or an insulin pump), decreasing the risk of hypoglycemic episodes. Insulin glargine may be a useful new option for meeting overnight insulin requirements, although most patients will require a rapid-acting insulin such as insulin lispro with or before meals for optimal management of blood glucose levels.

Insulin Self-Association and the Relationship to Pharmacokinetics and Pharmacodynamics

The treatment of type 1 diabetes requires multiple, daily injections of insulin. While many improvements involving formulation adjustments have been made in an attempt to optimize therapy, clinical experience indicates that the commercially available insulin preparations used for treatment have significant limitations. One principal deficiency relates to poor simulation of the physiological insulin secretion pattern, making achieving normalization of blood glucose concentrations difficult. Endogenous insulin secretion in nondiabetic subjects is characterized by a pulsatile profile that displays multiple, meal-stimulated phases and low basal concentrations between meals and overnight. Optimal diabetes therapy, therefore, requires insulin preparations that display a rapid onset of action with corresponding rapid clearance to provide for meal ingestion as well as preparations that can maintain a sustained, peakless profile for basal requirements. Recent efforts in pharmaceutical research have used the concept of rational-based design of the insulin molecule in an attempt to produce preparations that display more ideal pharmacological profiles. Using detailed structural information obtained from X-ray crystallographic studies to guide design strategies and exploit the nonrestrictive synthetic capabilities of recombinant DNA technology, researchers have prepared a number of insulin analogs that display a reduced propensity towards self-association. Clinical evaluations have shown that these so called "monomeric" analogs better mimic the meal-stimulated pharmacokinetics of insulin secretion observed in nondiabetics. Two monomeric insulin analog preparations have successfully obtained regulatory approval and are now commercially available. Efforts to produce optimized basal-acting insulin analogs have lagged behind. While some of these analogs have been engineered using recombinant DNA technology, design strategies in many cases exploit physicochemical properties of insulin other than self-association. One basal insulin analog has recently received regulatory approval. This paper reviews insulin self-association and its relationship to pharmacokinetics and pharmacodynamics. Particular emphasis is placed on the approaches used to manipulate self-assembly resulting in meal-time insulin analogs that display optimal pharmacological properties. Other design strategies used to develop improved basal insulin preparations are also considered.