Effects of initiation and titration of a single pre-prandial dose of insulin glulisine while continuing titrated insulin glargine in type 2 diabetes: a 6-month 'proof-of-concept' study

Aim: Stepwise intensification of insulin treatment to match the progressive decline of endogenous insulin secretion has been shown to be an effective management strategy in type 2 diabetes mellitus (T2DM). The efficacy of initiating and titrating a single bolus dose of insulin glulisine to baseline insulin glargine plus oral hypoglycaemic agents (OHAs) was investigated. Methods: This was a 6‐month, parallel‐group, randomized, open‐label, Phase IV study conducted in the US, UK and Russia. People with T2DM (HbA_1c 7.5–9.5%) using any basal insulin underwent a 3‐month run‐in period on insulin glargine titrated to optimize fasting blood glucose (BG) control. Those with HbA_1c >7.0% were randomized to either continue prior therapy (n = 57) or to add a single dose of insulin glulisine (n = 49) immediately prior to the main meal for a further 3 months. Two different titration algorithms were employed for the bolus dose, targeting 2‐h postprandial BG ≤135 mg/dL (≤7.5 mmol/l; Russia and UK) or pre‐meal/bedtime BG 100–120 mg/dl (5.5–6.7 mmol/l; US). Results: HbA_1c and fasting plasma glucose levels decreased during the run‐in period. In the 3 months after randomization, more participants in the basal‐plus‐bolus group reached HbA_1c <7.0% than the basal‐only control group (22.4 vs. 8.8%; p < 0.05), with significantly greater reduction of HbA_1c (?0.37 vs. ?0.11%; p = 0.0290). Rates of hypoglycaemia and mean weight change were comparable between the treatment groups. Conclusions: In people with T2DM inadequately controlled on basal insulin plus OHAs, adding a single injection of insulin glulisine prior to the main meal significantly improves glucose control without undesired side effects.     

Role of incretin‐based therapies and sodium‐glucose co‐transporter‐2 inhibitors as adjuncts to insulin therapy in Type 2 diabetes,with special reference to IDegLira

The progressive nature of Type 2 diabetes necessitates treatment intensification over time in order to maintain glycaemic control, with many patients ultimately requiring insulin therapy. While insulin has unlimited potential efficacy, its initiation is often delayed and improvements in glycaemic control are typically accompanied by weight gain and an increased risk of hypoglycaemia, particularly as HbA_1c approaches and falls below target levels. This may account for the sub‐optimal control often achieved after insulin initiation. Combining insulin with antihyperglycaemic therapies that have a low risk of hypoglycaemia and are weight‐neutral or result in weight loss is a therapeutic strategy with the potential to improve Type 2 diabetes management. Although the effects differ with each individual class of therapy, clinical trials have shown that adding a glucagon‐like peptide‐1 receptor agonist, dipeptidyl peptidase‐4 inhibitor or sodium‐glucose co‐transporter‐2 inhibitor to insulin regimens can offer a significant reduction in HbA_1c without substantially increasing hypoglycaemia risk, or weight. The evidence and merit of each approach are reviewed in this paper. Once‐daily co‐formulations of a basal insulin and a glucagon‐like peptide‐1 receptor agonist have been developed (insulin degludec/liraglutide) or are under development (lixisenatide/insulin glargine). Insulin degludec/liraglutide phase III trials and a lixisenatide/insulin glargine phase II trial have shown robust HbA_1c reductions, with weight loss and a low risk of hypoglycaemia. With insulin degludec/liraglutide now approved in Europe, an important consideration will be the types of patients who may benefit most from a fixed‐ratio combination; this is discussed in the present review, and we also take a look toward future developments in the field.     

Introducing a simplified approach to insulin therapy in type 2 diabetes: a comparison of two single‐dose regimens of insulin glulisine plus insulin glargine and oral antidiabetic drugs

Aim: To investigate whether the addition of a single bolus of insulin glulisine (glulisine), administered at either breakfast or main mealtime, in combination with basal insulin glargine (glargine) and oral antidiabetic drugs (OADs), provides equivalent glycaemic control in patients with type 2 diabetes, irrespective of the time of glulisine injection. Methods: A national, multicentre, randomized, open‐label, parallel‐group study of 393 patients with type 2 diabetes who were suboptimally controlled [haemoglobin A_1c (HbA_1c) > 6.5–9.0% and fasting blood glucose (BG) ≤6.7 mmol/l] on their previous glargine and OAD regimen. A single injection of glulisine was added, either at breakfast or at main mealtime, to their existing therapy. Results: The per‐protocol group (n = 316) showed improved HbA_1c (baseline vs. end‐point) in the breakfast (7.4 vs. 7.0%; p < 0.0001) and main mealtime groups (7.3 vs. 6.9%; p < 0.0001). Glulisine given at breakfast was equally effective in controlling HbA_1c as glulisine given at the main mealtime [adjusted HbA_1c mean difference (95% confidence interval): 0.0481% (–0.115 to 0.211); p < 0.0001 for equivalence]. Overall, 30.7% of patients achieved HbA_1c≤6.5% at end‐point but slightly more patients met this target in the main mealtime group vs. the breakfast group (33.8 vs. 27.8%; p = NS). This trend continued and was more marked when considering only those patients with HbA_1c >7.0% at baseline and who reached HbA_1c≤7.0% at end‐point (44.1% overall), with 52.2 and 36.5% for main mealtime and breakfast groups, respectively (p = 0.028). Most postprandial BG values improved within each group, while the number of hypoglycaemias was low and comparable between the two treatment groups. Conclusions: A single bolus of glulisine, added to glargine and OADs, resulted in significantly improved HbA_1c levels, irrespective of whether glulisine was administered at breakfast or at main mealtime. These results may represent a simplified and effective approach to treatment intensification in type 2 diabetes patients.     

Prevalence and reasons for insulin refusal in Bangladeshi patients with poorly controlled Type 2 diabetes in East London

Aims To determine the prevalence and reasons for refusal to commence insulin in Bangladeshi patients with Type 2 diabetes. Methods A survey of 212 Bangladeshi patients seen in a hospital diabetes unit, with poor glycaemic control (HbA_1c≥ 8.0%) on maximum oral glucose‐lowering therapy, in whom insulin was deemed necessary. Patients who refused insulin were invited to attend focus groups. Data were analysed by thematic content analysis using the constant comparative method. Results Of 212 patients offered insulin, 122 (57.5%) commenced insulin immediately, 47 (22.1%) started insulin within 6 months and 43 (20.3%) refused to commence insulin despite repeated counselling. Thirty‐six (83.7%) of those who refused insulin agreed to participate in focus groups. Reasons for insulin refusal included: disease severity—perceptions that requirement for insulin was an indicator of a more serious stage of their condition; insulin leading to premature death—common suggestion that commencing insulin led to early death; loss of control—including fear of hypoglycaemia, weight gain, loss of independence and reliance on others to give insulin or look for signs of hypoglycaemia; lack of perception of benefits—poor perception of the benefits of improved glycaemic control on quality of life and cardiovascular risk; needle anxiety—a significant proportion of subjects conveyed concern over frequent injections. Conclusions Insulin refusal is common in Bangladeshi subjects with Type 2 diabetes and poor glycaemic control. A number of factors contribute to this, and methods to overcome the barriers to insulin therapy need to be sought.     

Stepwise intensification of insulin therapy in Type 2 diabetes management—exploring the concept of the basal‐plus approach in clinical practice

Basal insulin provides an effective method for initiating insulin therapy in people with Type 2 diabetes, resulting in significant improvements in glycaemic control, lower rates of hypoglycaemia and less weight gain than either prandial or premixed insulin regimens. However, the progressive nature of Type 2 diabetes and the inability of basal insulin to correct excessive postprandial glucose excursions mean that insulin therapy will eventually need to be intensified, typically by adding prandial insulin as part of a basal–bolus or premixed insulin regimen. The aim of this review is to summarize recent clinical evidence for a staged ‘basal‐plus’ strategy for insulin intensification where one, two or three prandial insulin injections are added to basal insulin according to individual need. In the early stages of insulin therapy, most individuals seem to achieve favourable glycaemic control with basal insulin alone, or in combination with a single prandial insulin injection. The addition of a single prandial insulin injection at the largest meal is well tolerated and associated with significant improvements in glycated haemoglobin (HbA_1c), low rates of hypoglycaemia and limited weight gain. More people achieve recommended HbA_1c targets with a basal‐plus strategy, compared with twice‐daily premixed insulin therapy, with lower rates of hypoglycaemia. The data indicate that a step‐by‐step approach with the basal‐plus strategy is a promising alternative method of insulin intensification that allows for individualization of treatment and may delay progression to a full basal–bolus insulin replacement therapy for many individuals.     

Effects of insulin glulisine as mono- or add-on therapy in patients with type 2 diabetes mellitus

Aim: To evaluate the safety and efficacy of insulin glulisine (glulisine) with and without oral antidiabetic drugs (OAD; sulphonylurea or sulphonylurea + biguanide) relative to that of OAD alone in Japanese and Korean patients with inadequately controlled type 2 diabetes mellitus (T2DM). Methods: In an open, randomized, parallel‐group, comparative, controlled trial, 387 patients were randomized and treated with glulisine + OAD (n = 130), glulisine monotherapy (n = 127) or OAD only (n = 130) for 16 weeks. Glulisine was self‐injected subcutaneously three times daily (0–15 minutes before meals) at a starting dose of ≥0.2 U/kg/day. Patients titrated the glulisine dose to achieve a 2‐h postprandial plasma glucose (2h‐PPG) level of 7.1–9.5 mmol/l (128–172 mg/dl) by administering at least one additional unit at each appropriate meal time if the 2h‐PPG level was > 9.5 and < 11.1 mmol/l (> 172 and < 200 mg/dl) and by administering at least two additional units if the 2h‐PPG level was ≥ 11.1 mmol/l (≥ 200 mg/dl). Therapy with OAD was continued at the stable baseline regimen. The primary efficacy endpoint was change in haemoglobin A_1c (HbA_1c) from baseline to endpoint in the intention‐to‐treat population. Results: At baseline, therapy with OAD was a sulphonylurea only and a sulphonylurea + a biguanide in approximately 24 and 76% of patients respectively. Both glulisine groups had larger reductions in adjusted mean HbA_1c than the OAD‐only group (glulisine + OAD, ?2.07%; glulisine monotherapy, ?1.25%; OAD only, ?0.61%). Superiority of glulisine + OAD and glulisine monotherapy vs. OAD only was shown by differences in adjusted mean HbA_1c change from baseline values of ?1.46% (p < 0.0001) and ?0.64% (p < 0.0001) respectively. Both glulisine groups had better 2h‐PPG control than the OAD‐only group. Mean daily glulisine doses increased from baseline to endpoint (glulisine + OAD, 13.3–22.5 U; glulisine monotherapy, 14.2–38.0 U). The rate of all symptomatic hypoglycaemia events per patient‐year in the entire treatment phase was 11.9 in the glulisine + OAD group, 8.8 in the glulisine monotherapy group and 1.7 in the OAD‐only group. There was only one event of severe hypoglycaemia, which occurred in the glulisine + OAD group. Efficacy and safety were similar in Japanese and Korean subpopulations. Conclusions: Both glulisine + OAD and glulisine monotherapy were well tolerated and effective for Japanese and Korean patients with T2DM mellitus inadequately controlled by OAD therapy alone.     

Less weight gain and hypoglycaemia with once‐daily insulin detemir than NPH insulin in intensification of insulin therapy in overweight Type 2 diabetes patients—The PREDICTIVE™ BMI clinical trial1

Objective To assess weight change when once‐daily insulin detemir (detemir) or neutral protamine Hagedorn insulin (NPH) are used in already overweight Type 2 diabetes patients requiring intensified insulin therapy. Research design and methods This 26‐week randomized, controlled trial included adults with Type 2 diabetes [glycated haemoglobin (HbA_1c) 7.5–11.0%, body mass index (BMI) 25–40 kg/m²] who had received two daily doses of insulin (at least one a premix) for ≥ 3 months. Subjects received either detemir (n = 125) or NPH (n = 146) once daily in the evening and insulin aspart at main meals. Concomitant treatment with metformin was allowed. Basal insulin was titrated to a pre‐breakfast plasma glucose target of 6.1 mmol/l without unacceptable hypoglycaemia. Insulin aspart was also titrated (target, postprandial glucose ≤ 10.0 mmol/l without unacceptable hypoglycaemia). Results At 26 weeks, weight had increased significantly less with detemir (0.4 kg) than with NPH (1.9 kg; difference 1.5 kg, P < 0.0001). BMI increase was also less with detemir than with NPH (difference 0.6 kg/m², P < 0.0001). HbA_1c decreased from 8.9 to 7.8% (detemir) and from 8.8 to 7.8% (NPH; not significant for between‐treatment difference). Incidence of hypoglycaemia was lower with detemir [relative risks 0.62 (all events) and 0.43 (nocturnal); P < 0.0001 for both]. Conclusions PREDICTIVE? BMI was the first study to examine the effect of once‐daily detemir with weight as the primary endpoint in a large population of overweight Type 2 diabetes patients. Use of once‐daily detemir for intensification of insulin therapy resulted in less weight gain, less hypoglycaemia and equivalent glycaemic control compared with NPH.     

Comparison between a basal-bolus and a premixed insulin regimen in individuals with type 2 diabetes–results of the GINGER study

Aim: To compare the efficacy and safety of an intensified insulin regimen, using insulin glargine (glargine) once daily and pre‐meal insulin glulisine (glulisine) (basal‐bolus), with a conventional therapy, using premixed insulin (premix) twice daily. Methods: This 52‐week, open‐label, randomized, multinational, multicentre trial included 310 subjects with type 2 diabetes (T2D) on premix, with or without metformin, who were randomized to a basal‐bolus regimen with glargine and glulisine (n = 153; mean ± s.d. age 60.2 ± 7.5 years; HbA1c 8.6 ± 0.8%; weight 87.0 ± 15.1 kg; T2D duration 12.8 ± 5.8 years) or twice‐daily premix (n = 157; age 60.9 ± 7.8 years; HbA1c 8.5 ± 0.9%; weight 84.3 ± 15.0 kg; T2D duration 12.5 ± 6.8 years). The primary endpoint was change in HbA1c from baseline to endpoint. Results: Mean decrease in baseline‐to‐endpoint HbA1c for basal‐bolus vs. premix was ?1.31 vs. ?0.80% (difference: ?0.476%; 95% Cl: ?0.714, ?0.238; p = 0.0001, ancova ). More subjects reached HbA1c ≤ 7.0% in the basal‐bolus group than in the premix group [68 (46.6%) vs. 43 (27.9%); p = 0.0004], while they also experienced significantly lower mean ± s.d. daytime (?2.7 ± 2.3 vs. ?2.3 ± 2.5 mmol/l; p = 0.0033) and postprandial (?3.1 ± 2.6 vs. ?2.5 ± 2.8 mmol/l; p < 0.0001) blood glucose. Endpoint daily insulin doses were 98.0 ± 48.7 vs. 91.3 ± 44.3 IU (p = 0.2104); mean weight gain was +3.6 ± 4.0 vs. +2.2 ± 4.5 kg (p = 0.0073). Mean number of overall hypoglycaemic events with basal‐bolus and premix was 13.99 and 18.54 events/patient year, respectively (difference: ?3.90; 95% CI: ?10.40, 2.60; p = 0.2385). Conclusions: An intensified basal‐bolus regimen using glargine/glulisine results in a significantly superior glycaemic control vs. premix therapy in a population with long‐standing insulin‐treated T2D, with no increase in the rates of hypoglycaemia.     

Use of insulin in type 2 diabetes: What we learned from recent clinical trials on the benefits of early insulin initiation

The majority of people with type 2 diabetes mellitus (T2DM) require insulin therapy to maintain HbA_1c levels < 7% during the first decade of diagnosis. Large prospective trials investigating the cardiovascular (CV) benefits of intensive glycaemic control have produced inconsistent results; however, meta-analyses have suggested that intensive glycaemic control provides both micro- and macrovascular benefits. The ORIGIN study investigated the impact of basal insulin glargine therapy targeting ≤ 5.3 mmol/L for fasting plasma glucose compared with standard care on CV outcomes in people with pre- or early diabetes, and demonstrated a neutral effect on CV outcomes with long-term use of insulin glargine early in the course of diabetes, with a low rate of severe hypoglycaemia and modest weight gain. The EARLY, GLORY and EASIE studies also demonstrated that insulin use earlier in the treatment pathway led to improved glycaemic control, reduced weight gain and fewer hypoglycaemic episodes than when insulin was added later in the course of disease. The beneficial effect of early transient intensive insulin therapy (TIIT) at diagnosis has been demonstrated in a number of trials; it rapidly limits the damage caused by gluco- and lipotoxicity, improving residual β-cell function and potentially slowing disease progression. The evidence suggests that people newly diagnosed with T2DM and HbA_1c > 9% should be given early TIIT to achieve normoglycaemia within weeks, after which standard care should then be adopted. Insulin use earlier in the treatment pathway should be considered, as it reduces the risk of hypoglycaemia as well as allows β-cell rest, which can help preserve β-cell function.     

Preprandial vs. postprandial insulin lispro-a comparative crossover trial in patients with Type 1 diabetes.

AIMS: Administration of bolus insulin after eating may be a useful therapeutic option for some patients. This 6-month, crossover study compared metabolic effects of routine use of preprandial vs. postprandial injection of bolus insulin lispro. METHODS: Thirty-one patients with Type 1 diabetes injected insulin lispro either preprandially or postprandially for a 3-month period followed by the alternate regimen for a further 3 months. HbA1c, fructosamine and eight-point self-determined blood glucose profiles were measured and analysed using an anova model appropriate for a crossover design. RESULTS: Mean HbA1c decreased slightly from baseline with preprandial (-0.15 +/- 0.41%) and increased slightly with postprandial (0.11 +/- 0.48%) insulin lispro so that there was a significant (P = 0.008) difference between treatments in final HbA1c level. Mean fructosamine also decreased slightly with preprandial (-15 +/- 31 micro mol/l) but was almost unchanged (1 +/- 39 micro mol/l) with postprandial insulin lispro. Overall daily blood glucose was not different (P = 0.312) for preprandial compared with postprandial administration. However, mean preprandial glucose was lower (7.5 +/- 2.01 vs. 6.6 +/- 1.22 mmol/l; P = 0.026), whereas mean postprandial glucose was higher (7.7 +/- 1.8 vs. 8.7 +/- 2.1 mmol/l; P = 0.031) with postprandial insulin lispro administration. Mean blood glucose excursions were higher with postprandial compared with preprandial insulin lispro, indicating greater daily fluctuations. No difference in incidence of hypoglycaemia was observed with the two treatment regimens. CONCLUSIONS: Postprandial insulin lispro administration appeared to be an acceptable treatment regimen and may be of benefit in certain situations. However, the benefits of postprandial administration may have to be balanced against poorer glycaemic control with continuous long-term use.     

Stabilizing effect of exenatide in a patient with C‐peptide‐negative diabetes mellitus

Background Exenatide is an incretin mimetic licensed for treatment of Type 2 diabetes poorly controlled despite maximally tolerated doses of oral therapy. Similar in structure to the natural incretin hormone glucagon‐like peptide 1 (GLP‐1), it helps restore underlying pathophysiological abnormalities. Case report We report the successful use of exenatide, combined with insulin, in a 66‐year‐old woman initially diagnosed with Type 2 diabetes in 1989 but now exhibiting a Type 1 phenotype. Diet, lifestyle advice and oral glucose‐lowering agents were commenced but persisting poor control necessitated insulin therapy in 2005. She later presented twice in diabetic ketoacidosis, suggesting conversion to a Type 1 phenotype (postprandial C‐peptide < 94 pmol/l). Despite differing insulin regimens, control remained poor with frequent hyperglycaemic and hypoglycaemic excursions, severely impairing quality of life. Whilst an inpatient in 2007 [glycated haemoglobin (HbA_1c) 10.2%, body mass index (BMI) 31.5 kg/m²] exenatide was commenced in an attempt to stabilize glycaemic control. Dramatic improvements were seen and continued. Eight months later, HbA_1c had fallen by 2% with an 8‐kg weight loss and 10‐unit reduction in daily insulin dose. Quality of life dramatically improved. C‐peptide remains undetectable. Conclusions This patient with features of both Type 1 and Type 2 diabetes benefited greatly from exenatide with insulin therapy. The improvement seen in glycaemic control could not be attributable to enhanced insulin secretion but could be as a result of a combination of the other incretin effects (postprandial glucagon suppression, delayed gastric emptying and weight loss secondary to increased satiety) all improving insulin sensitivity, reducing insulin dose and smoothing control.     

Treat‐to‐target trials: uses,interpretation and review of concepts

Treat‐to‐target trial designs compare investigational insulins with a standard insulin. Treat‐to‐target trials force‐titrate insulin dosages to achieve a prespecified treatment goal. With comparable glycaemic control, comparisons of safety endpoints such as hypoglycaemia can be made to establish the risk‐benefit profile of the new insulin. Glargine versus NPH showed comparable A1C reductions; however, A1C <7% without associated nocturnal hypoglycaemia was reached in more patients on glargine and overall hypoglycaemia was lower. Detemir versus glargine showed non‐inferiority between the groups; however, with less weight gain and more injection site reactions with detemir. Detemir/aspart versus glargine/aspart showed non‐inferiority between the treatments, however, with less weight gain in the detemir group but comparable risk of hypoglycaemia. Degludec in combination with aspart versus glargine/aspart showed comparable A1C reductions. However, degludec‐treated patients had less overall hypoglycaemia and less nocturnal hypoglycaemia. Because insulin titrations are guided by goal attainment with each treatment, treat‐to‐target trials enable clinicians to determine differences in non‐glycaemic treatment effects, such as rates of hypoglycaemia and weight gain, at the same level of glycaemic control.     

Efficacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, double-blind, non-inferiority trial

Aim: To evaluate the efficacy and safety of adding sitagliptin or glimepiride to the treatment regimen of patients with type 2 diabetes mellitus and inadequate glycaemic control on metformin monotherapy. Methods: Patients with type 2 diabetes and an HbA_1c of 6.5–9.0% while on a stable dose of metformin (≥1500 mg/day) combined with diet and exercise for at least 12 weeks were randomized in a double‐blind manner to receive either sitagliptin 100 mg daily (N = 516) or glimepiride (starting dose 1 mg/day and up‐titrated, based upon patient's self‐monitoring of blood glucose results, to a maximum dose of up to 6 mg/day) (N = 519) for 30 weeks. The primary analysis assessed whether sitagliptin is non‐inferior to glimepiride in reducing HbA_1c at week 30 (based on the criterion of having an upper bound of the 95% CI less than the prespecified non‐inferiority bound of 0.4%). Results: The mean baseline HbA_1c was 7.5% in both the sitagliptin group (n = 443) and the glimepiride group (n = 436). After 30 weeks, the least squares (LS) mean change in HbA_1c from baseline was ?0.47% with sitagliptin and ?0.54% with glimepiride, with a between‐group difference (95% CI) of 0.07% (?0.03, 0.16). This result met the prespecified criterion for declaring non‐inferiority. The percentages of patients with an HbA_1c < 7.0% at week 30 were 52 and 60% in the sitagliptin and glimepiride groups, respectively. The LS mean change in fasting plasma glucose from baseline (95% CI) was ?0.8 mmol/l (?1.0, ?0.6) with sitagliptin and ?1.0 mmol/l (?1.2, ?0.8) with glimepiride, for a between‐group difference (95% CI) of 0.2 mmol/l (?0.1, 0.4). The percentages of patients for whom hypoglycaemia was reported were 7% in the sitagliptin group and 22% in the glimepiride group (percentage‐point difference = ?15, p < 0.001). Relative to baseline, sitagliptin was associated with a mean weight loss (?0.8 kg), whereas glimepiride was associated with a mean weight gain (1.2 kg), yielding a between‐group difference of ?2.0 kg (p < 0.001). Conclusions: In patients with type 2 diabetes and inadequate glycaemic control on metformin monotherapy, the addition of sitagliptin or glimepiride led to similar improvement in glycaemic control after 30 weeks. Sitagliptin was generally well tolerated. Compared to treatment with glimepiride, treatment with sitagliptin was associated with a lower risk of hypoglycaemia and with weight loss versus weight gain ( ClinicalTrials.gov : NCT00701090).     

Patient-directed titration for achieving glycaemic goals using a once-daily basal insulin analogue: an assessment of two different fasting plasma glucose targets - the TITRATETM study

Aims: To compare efficacy and safety of two fasting plasma glucose (FPG) titration targets [4.4–6.1 mmol/l (80–110 mg/dl) and 3.9–5.0 mmol/l (70–90 mg/dl)] using a patient‐directed, treat‐to‐target algorithm for once‐daily basal insulin in insulin‐naïve subjects with type 2 diabetes suboptimally treated with oral antidiabetes drugs (OADs). Methods: In this 20‐week, randomized, controlled, open‐label, multicentre, treat‐to‐target study, 244 insulin‐naïve subjects with type 2 diabetes, HbA_1c≥7.0 and ≤9.0% on OAD treatment, were randomized (1 : 1) to one of two treatment arms using 3.9–5.0 or 4.4–6.1 mmol/l FPG as titration targets. Once‐daily insulin detemir doses were adjusted using algorithm‐guided patient‐directed titration to achieve target FPG values. Results: Overall, the combined treatment groups achieved a mean HbA_1c level of 6.9% at the end of the study. Substantial reductions in HbA_1c were seen in both treatment groups, with the majority of subjects in both titration groups at the end of the study achieving the American Diabetes Association (ADA)‐recommended HbA_1c level of <7%. In the 3.9–5.0 mmol/l FPG target treatment group, HbA_1c values decreased from a baseline mean of 8.0% to 6.8% at 20 weeks. In the 4.4–6.1 mmol/l FPG target group, HbA_1c values decreased from 7.9% at baseline to 7.0% at 20 weeks (Intention to treat ‐ last observation carried forward data set). These decreases were significantly different between the two treatment groups (Least squares mean difference = ?0.271, 95% CI ?0.441 to ?0.101, p = 0.0019), favouring the FPG target of 3.9–5.0 mmol/l vs. the 4.4–6.1 mmol/l target. At the end of the study period, 64.3% of subjects in the 3.9–5.0 mmol/l treatment group achieved HbA_1c levels <7% compared with 54.5% of subjects in the 4.4–6.1 mmol/l group (95% CI 1.03–3.37, odds ratio 1.86, p = 0.04). Insulin detemir dosing patterns were similar between treatment groups, with the 3.9–5.0 mmol/l group using slightly greater doses throughout the study period (0.57 U/kg vs. 0.51 U/kg at the end of the study). Overall rates of hypoglycaemia episodes were low and were comparable between treatment groups (7.73 and 5.27 events/subject/year for the 3.9–5.0 and 4.4–6.1 mmol/l groups, respectively). A single event of major hypoglycaemia was reported in the 3.9–5.0 mmol/l group. Mean weight changes from baseline to the end of the study were small and did not differ significantly between treatment groups. Conclusions: The 3.9–5.0 mmol/l FPG target showed superior efficacy compared with the 4.4–6.1 mmol/l target, although both FPG titration targets resulted in substantial reductions of HbA_1c in patients with type 2 diabetes using a patient‐directed insulin titration algorithm. A majority of subjects in both titration groups achieved the ADA‐recommended guideline of <7% HbA_1c at the end of the study with low rates of hypoglycaemia. These data indicate that lowering the fasting glucose target using a self‐directed titration algorithm with once‐daily detemir is safe and increases the likelihood of achieving the target level of HbA_1c. Indeed, using this approach, a majority of patients can achieve an HbA_1c of <7%.     

Does serum 1,5‐anhydroglucitol establish a relationship between improvements in HbA1c and postprandial glucose excursions? Supportive evidence utilizing the differential effects between biphasic insulin aspart 30 and insulin glargine

Aim To investigate the relationship between changes in glycated haemoglobin (HbA_1c) and postprandial glucose excursions on 1,5‐anhydroglucitol (1,5‐AG) in patients with Type 2 diabetes, utilizing the differential effects between biphasic insulin aspart 30 (BIAsp 30) or insulin glargine (IGlar) on postprandial glucose (PPG) levels. Methods 1,5‐AG was measured using the GlycoMark® assay at baseline and after 12 and 28 weeks in the INITiation of Insulin to reach HbA_1c Target (INITIATE) study of 233 patients randomized to either BIAsp 30 or IGlar. Results Baseline 1,5‐AG was low and not significantly different (4.9 ± 3.5 and 4.3 ± 2.6 µg/ml in the BIAsp 30 and IGlar groups, respectively). After 28 weeks, the levels of 1,5‐AG were higher in the BIAsp 30 than in the IGlar group (13.4 vs. 11.1 µg/ml, P = 0.008) and change from baseline was 25% greater with BIAsp 30 than IGlar (8.4 vs. 6.7 µg/ml, P = 0.011). 1,5‐AG levels increased as a function of decreasing HbA_1c or the average change in postprandial plasma glucose (PPG_ave) with significant relationships for 1,5‐AG/ HbA_1c vs. HbA_1c or 1,5‐AG/PPG_ave vs. PPG_ave (both P < 0.0001), respectively. Conclusions As reported in previous publications, 1,5‐AG reflects ambient glycaemic control and increases with reductions in HbA_1c and postprandial glucose. The greater reductions in postprandial excursion achieved with BiAsp 30 compared with glargine were associated with greater increases in 1,5‐AG. Even moderate elevations in HbA_1c substantially lower 1,5‐AG, suggesting that it can be most discriminating in identifying patients with excessive postprandial glucose excursions at HbA_1c levels that approach the upper end of the normal range.     

Comparison of twice-daily injections of biphasic insulin lispro and basal-bolus therapy: glycaemic control and quality-of-life of insulin-naïve type 2 diabetic patients

Objective: The aim of this study was to evaluate twice‐daily injections of biphasic insulin lispro vs. basal–bolus (BB) therapy with regard to quality‐of‐life (QOL) and glycaemic control in insulin‐naïve type 2 diabetic patients. Methods: Twenty‐eight patients with type 2 diabetes were randomized to receive either twice‐daily 50/50 premixed insulin lispro (Mix50 group) or BB (NPH insulin at bedtime and preprandial insulin lispro) therapy (BB group) for 12 weeks. Glycated haemoglobin (HbA1C), 1,5‐anhydroglucitol (1,5‐AG), blood plasma glucose level, body mass index (BMI), daily total insulin dosage and insulin therapy–related QOL (ITR‐QOL) were studied. Results: ITR‐QOL was significantly better in the Mix50 than in the BB group (103.1 ± 9.8 vs. 90.6 ± 19.4; p < 0.05). HbA_1c improved in both groups (from 11.1 ± 2.1 to 6.9 ± 1.0% with Mix50 vs. from 11.0 ± 2.3 to 6.6 ± 0.8% with BB therapy). Conclusion: These results might suggest that twice‐daily injections of premixed rapid‐acting insulin analogue therapy could achieve good glycaemic control and better QOL compared with BB therapy in insulin‐naïve type 2 diabetes.     

Comparison of insulin detemir and insulin glargine in subjects with Type 1 diabetes using intensive insulin therapy.

AIMS: To compare glycaemic control and risk of hypoglycaemia of twice-daily insulin detemir with once-daily insulin glargine in subjects with Type 1 diabetes. METHODS: In this 26-week, multicentre, open-label, parallel-group trial, 320 subjects with Type 1 diabetes received either insulin detemir twice daily or insulin glargine once daily. each in combination with premeal insulin aspart. RESULTS: After 26 weeks, HbA(1c) had decreased from 8.8 to 8.2% in the insulin detemir group and from 8.7 to 8.2% in the insulin glargine group. Home-measured fasting plasma glucose (PG) was lower with insulin glargine than with insulin detemir (7.0 vs. 7.7 mmol/l, P < 0.001). The overall shape of the home-measured nine-point PG profiles was comparable between treatments (P = 0.125). Overall, there was no significant difference in within-subject variation in PG (P = 0.437). Within-subject variation in predinner PG was lower with insulin detemir than with insulin glargine (P < 0.05). The overall risk of hypoglycaemia was similar with no differences in confirmed hypoglycaemia. However, the risk of severe and nocturnal hypoglycaemia was 72% and 32%, respectively, lower with insulin detemir than with insulin glargine (P < 0.05). Body weight gain was not significantly different comparing insulin detemir and insulin glargine (0.52 kg vs. 0.96 kg, P = 0.193). CONCLUSIONS: Treatment with twice-daily insulin detemir or once-daily insulin glargine, each in combination with insulin aspart, resulted in similar glycaemic control. The overall risk of hypoglycaemia was comparable, whereas the risks of both severe and nocturnal hypoglycaemia were significantly lower with insulin detemir.     

A comparison of intensive mixture therapy with basal insulin therapy in insulin-naïve patients with type 2 diabetes receiving oral antidiabetes agents

Aim: In patients with type 2 diabetes, insulin therapy is commonly initiated with either a single dose of basal insulin or twice‐daily premixed (basal plus prandial) insulin despite no widely accepted recommendation. We compared the glycaemic control, as measured by a change in HbA1c, of intensive mixture therapy (IMT), a basal plus prandial regimen using insulin lispro mixture 50/50 (50% lispro and 50% NPL) before breakfast and lunch and insulin lispro mixture 25/75 (25% lispro and 75% NPL) before dinner, vs. once‐daily insulin glargine therapy, while continuing patients on oral antidiabetes medications. Methods: Following inadequate glycaemic control (HbA1c 1.2–2.0 times the upper limit of normal) and at least 2 months of two or more oral antidiabetes agent therapy, 60 insulin‐naïve patients with type 2 diabetes were randomized to one of the insulin regimens for 4 months with crossover to the alternative regimen for an additional 4 months. Glycaemic goals were preprandial blood glucose <120 mg/dl (6.7 mmol/l) and 2‐h postprandial blood glucose <180 mg/dl (10.0 mmol/l). The insulin dose was optimized by investigators without forced titration. Results: Mean prestudy (baseline) HbA1c for all patients was 9.21 ± 1.33% (±s.d.). IMT compared to glargine resulted in both a lower endpoint in HbA1c (7.08 ± 0.11% vs. 7.34 ± 0.11%; p = 0.003) and a greater change in HbA1c from pretherapy (?1.01 ± 0.10% vs. ?0.75 ± 0.10%; p = 0.0068). Forty‐four per cent of patients receiving IMT and 31% of patients receiving insulin glargine achieved HbA1c ≤ 7%. Two‐hour postprandial glucose values (for all three meals) and predinner glucose values were significantly less with IMT than with insulin glargine (p = 0.0034, 0.0001, 0.0066 and 0.0205). Overall hypoglycaemia throughout the complete treatment period was infrequent (IMT vs. Glargine: 3.98 ± 4.74 vs. 2.57 ± 3.22 episodes/patient/30 days, p = 0.0013), and no severe hypoglycaemia was observed during the study with either therapy. There was no difference in nocturnal hypoglycaemia between the two therapies. The mean insulin dose at the end of therapy was greater for IMT than for once‐daily insulin glargine (0.353 ± 0.256 vs. 0.276 ± 0.207 IU/kg, p = 0.0107). Conclusions: In combination with oral antidiabetes agents, multiple daily injections of a basal plus prandial insulin IMT regimen (using premixed insulin lispro formulations) resulted in greater improvements and a lower endpoint in HbA1c compared with a basal‐only insulin regimen. IMT also resulted in improved postprandial blood glucose control at each meal and enabled administration of a greater daily dose of insulin, which most likely contributed to these lower HbA1c measures. This greater reduction in HbA1c with IMT is accompanied by a small increased occurrence of mild hypoglycaemia but without any severe hypoglycaemia. Greater consideration should be given to initiating insulin as a basal plus prandial regimen rather than a basal‐only regimen.     

Safety and efficacy of glargine compared with NPH insulin for the treatment of Type 2 diabetes: a meta‐analysis of randomized controlled trials

Aims We systematically analysed evidence from randomized controlled trials (RCTs) examining the safety and efficacy of neutral protamine Hagedorn (NPH) insulin and glargine in the management of adults with Type 2 diabetes. Methods Studies were identified by searching medline (1966–March 2007), embase (1974–2007), American Diabetes Association abstract database and the Cochrane Central Register of Controlled Trials using Medical Subject Headings (MeSH) diabetes mellitus, Type 2, insulin, insulin isophane, hypoglycaemic agents and the keywords glargine and NPH. Data on study design, participants, fasting plasma glucose (FPG), glycated haemoglobin (HbA_1c), body weight and hypoglycaemia were independently abstracted by two investigators using a standardized protocol. Results Data from a total of 4385 participants in 12 RCTs were pooled using a random‐effects model. The mean net change (95% confidence interval) for FPG, HbA_1c and body weight for patients treated with NPH insulin as compared with glargine was 0.21 mmol/l (?0.02 to 0.45), 0.08% (?0.04 to 0.21) and ?0.33 kg (?0.61 to ?0.06), respectively, with negative values favouring NPH and positive values favouring glargine. More participants experienced symptomatic and nocturnal hypoglycaemia on NPH than glargine, but there was no significant difference in confirmed or severe episodes. Conclusions We identified no difference in glucose‐lowering between insulin glargine and NPH insulin, but less patient‐reported hypoglycaemia with glargine and slightly less weight gain with NPH in adults with Type 2 diabetes.     

Initiation of insulin glargine therapy in type 2 diabetes subjects suboptimally controlled on oral antidiabetic agents: results from the AT.LANTUS trial

Objective: For many patients with type 2 diabetes, oral antidiabetic agents (OADs) do not provide optimal glycaemic control, necessitating insulin therapy. Fear of hypoglycaemia is a major barrier to initiating insulin therapy. The AT.LANTUS study investigated optimal methods to initiate and maintain insulin glargine (LANTUS^®, glargine, Sanofi-aventis, Paris, France) therapy using two treatment algorithms. This subgroup analysis investigated the initiation of once-daily glargine therapy in patients suboptimally controlled on multiple OADs. Research Design and Methods: This study was a 24-week, multinational (59 countries), multicenter (611), randomized study. Algorithm 1 was a clinic-driven titration and algorithm 2 was a patient-driven titration. Titration was based on target fasting blood glucose ≤100 mg/dl (≤5.5 mmol/l). Algorithms were compared for incidence of severe hypoglycaemia [requiring assistance and blood glucose <50 mg/dl (<2.8 mmol/l)] and baseline to end-point change in haemoglobin A_1c (HbA_1c). Results: Of the 4961 patients enrolled in the study, 865 were included in this subgroup analysis: 340 received glargine plus 1 OAD and 525 received glargine plus >1 OAD. Incidence of severe hypoglycaemia was <1%. HbA_1c decreased significantly between baseline and end-point for patients receiving glargine plus 1 OAD (−1.4%, p < 0.001; algorithm 1 −1.3% vs. algorithm 2 −1.5%; p = 0.03) and glargine plus >1 OAD (−1.7%, p < 0.001; algorithm 1 −1.5% vs. algorithm 2 −1.8%; p = 0.001). Conclusions: This study shows that initiation of once-daily glargine with OADs results in significant reduction of HbA_1c with a low risk of hypoglycaemia. The greater reduction in HbA_1c was seen in patients randomized to the patient-driven algorithm (algorithm 2) on 1 or >1 OAD.