Insulin glargine versus sitagliptin in insulin-naive patients with type 2 diabetes mellitus uncontrolled on metformin (EASIE): a multicentre, randomised open-label trial.

BACKGROUND: In people with type 2 diabetes, a dipeptidyl peptidase-4 (DPP-4) inhibitor is one choice as second-line treatment after metformin, with basal insulin recommended as an alternative. We aimed to compare the efficacy, tolerability, and safety of insulin glargine and sitagliptin, a DPP-4 inhibitor, in patients whose disease was uncontrolled with metformin. METHODS: In this comparative, parallel, randomised, open-label trial, metformin-treated people aged 35-70 years with glycated haemoglobin A(1c) (HbA(1c)) of 7-11%, diagnosis of type 2 diabetes for at least 6 months, and body-mass index of 25-45 kg/m(2) were recruited from 17 countries. Participants were randomly assigned (1:1) to 24-week treatment with insulin glargine (titrated from an initial subcutaneous dose of 0·2 units per kg bodyweight to attain fasting plasma glucose of 4·0-5·5 mmol/L) or sitagliptin (oral dose of 100 mg daily). Randomisation (via a central interactive voice response system) was by random sequence generation and was stratified by centre. Patients and investigators were not masked to treatment assignment. The primary outcome was change in HbA(1c) from baseline to study end. Efficacy analysis included all randomly assigned participants who had received at least one dose of study drug and had at least one on-treatment assessment of any primary or secondary efficacy variable. This trial is registered at ClinicalTrials.gov, NCT00751114. FINDINGS: 732 people were screened and 515 were randomly assigned to insulin glargine (n=250) or sitagliptin (n=265). At study end, adjusted mean reduction in HbA(1c) was greater for patients on insulin glargine (n=227; -1·72%, SE 0·06) than for those on sitagliptin (n=253; -1·13%, SE 0·06) with a mean difference of -0·59% (95% CI -0·77 to -0·42, p<0·0001). The estimated rate of all symptomatic hypoglycaemic episodes was greater with insulin glargine than with sitagliptin (4·21 [SE 0·54] vs 0·50 [SE 0·09] events per patient-year; p<0·0001). Severe hypoglycaemia occurred in only three (1%) patients on insulin glargine and one (<1%) on sitagliptin. 15 (6%) of patients on insulin glargine versus eight (3%) on sitagliptin had at least one serious treatment-emergent adverse event. INTERPRETATION: Our results support the option of addition of basal insulin in patients with type 2 diabetes inadequately controlled by metformin. Long-term benefits might be expected from the achievement of optimum glycaemic control early in the course of the disease. FUNDING: Sanofi.

Dose accuracy of a reusable insulin pen using a cartridge system with an integrated plunger mechanism.

Pen injection devices are a common method of administering insulin for patients with diabetes. Pen devices must comply with guidelines prepared by the International Organization for Standardization, which include device dose accuracy and precision. OptiClik (sanofi-aventis) was developed to fulfil unmet needs of patients with diabetes, including: easier cartridge changing, clearer dose display and readability, and a larger dose of insulin to be delivered with a single injection. In this paper, the authors report on the dose accuracy of the OptiClik pen device, which uses a novel cartridge system with an integrated plunger for easier cartridge changing. The authors show that OptiClik accurately delivers a required dose of insulin, which is maintained over the lifetime of the pen. OptiClik offers a significant contribution to the treatment of diabetes.

Use of a basal-plus insulin regimen in persons with type 2 diabetes stratified by age and body mass index: A pooled analysis of four clinical trials.

AIMS: To evaluate the efficacy and safety of adding a single bolus dose of insulin glulisine to basal insulin ('basal-plus') in persons with type 2 diabetes. METHODS: Data from patients with poor glycemic control on oral antihyperglycemic drugs who were initiated on a 'basal-plus' regimen for up to 6 months were pooled from four randomized, multicenter studies. Glycated hemoglobin (HbA1c), fasting blood glucose, postprandial glucose (PPG), insulin dose and demographics were measured at baseline and end of study. RESULTS: 711 patients with a mean age of 59.9 years and a mean duration of diabetes of 11.0 years were included in the analysis population. A 'basal-plus' regimen was associated with significant decreases in HbA1c and PPG at 6 months, an increase in glargine and glulisine doses and small, but statistically significant, changes in body weight and BMI in all patient subsets. The proportion of patients with HbA1c<7% also increased in all populations studied, while the prevalence of severe hypoglycemia was low and did not significantly differ across patient groups. CONCLUSIONS: These results suggest that the use of 'basal-plus' can achieve a good therapeutic response with a low risk of hypoglycemia and weight gain, regardless of a patient's age or BMI.

Four-year evolution of insulin regimens, glycaemic control, hypoglycaemia and body weight after starting insulin therapy in type 2 diabetes across three continents.

AIMS: It is of interest to understand how insulin therapy currently evolves in clinical practice, in the years after starting insulin in people with type 2 diabetes. We aimed to describe this evolution prospectively over 4 years, to assist health care planning. METHODS: People who had started any insulin were identified from 12 countries on three continents. Baseline, then yearly follow-up, data were extracted from clinical records over 4 years. RESULTS: Of the 2999 eligible people, 2272 were followed over 4 years. When starting insulin, mean (SD) duration of diabetes was 10.6 (7.8) years, HbA1c 9.5 (2.0)% (80 [22]mmol/mol) and BMI 29.3 (6.3)kg/m(2). Initial insulin therapy was basal 52%, premix 23%, mealtime+basal 14%, mealtime 8% and other 3%; at 4 years, 30%, 25%, 33%, 2% and 5%, respectively, with 5% not on insulin. Insulin dose was 20.2U/day at the start and 45.8U/day at year 4. There were 1258 people (55%) on their original regimen at 4 years, and this percentage differed according to baseline insulin regimen. HbA1c change was -2.0 (2.2)% (-22 [24]mmol/mol) and was similar by final insulin regimen. Hypoglycaemia prevalence was <20% in years 1-4. Body weight change was mostly in year 1, and was very variable, mean +2.7 (7.5)kg at year 4. CONCLUSION: Different insulin regimens were started in people with differing characteristics, and they evolved differently; insulin dose, hypoglycaemia and body weight change were diverse and largely independent of regimen.

Insulin glargine compared with premixed insulin for management of insulin-naïve type 2 diabetes patients uncontrolled on oral antidiabetic drugs: the open-label, randomized GALAPAGOS study.

AIMS: Demonstrate superiority of insulin glargine (±glulisine) strategy versus premixed insulin strategy for percentage of patients reaching HbA1c <7% (<53 mmol/mol) at study end without any documented symptomatic hypoglycemia (bloof glucose [BG] ≤3.1 mmol/L) in type 2 diabetes (T2DM) patients failing oral agents. METHODS: This 24-week, open-label, multinational trial randomized patients to glargine OD or premix OD or BID, continuing metformin ± insulin secretagogue (IS). Second premix injection could be added any time; glulisine could be added with main meal in glargine OD patients with HbA1c ≥7% and fasting blood glucose (FBG) <7 mmol/L at week 12. IS was stopped with any second injection. Insulin titration targeted FBG ≤5.6 mmol/L. RESULTS: Modified intent-to-treat population comprised 923 patients (glargine, 462; premix, 461). Baseline characteristics were similar (mean T2DM duration: 9 years; HbA1c: 8.7% (72 mmol/mol); FBG: 10.4 mmol/L). Primary endpoint was achieved by 33.2% of glargine (±glulisine) and 31.4% of premix patients. Superiority was not demonstrated, but non-inferiority was (pre-specified margin: 25% of premix rate). More patients using premix achieved target (52.6% vs. 43.2%, p=0.005); symptomatic hypoglycemia was less with glargine (1.17 vs. 2.93 events/patient-year). CONCLUSIONS: Glargine (±glulisine) and premix strategies resulted in similar percentages of well-controlled patients without hypoglycemia, with more patients achieving target HbA1c with premix whereas overall symptomatic hypoglycemia was less with glargine.

Triple combination of insulin glargine, sitagliptin and metformin in type 2 diabetes: the EASIE post-hoc analysis and extension trial.

AIM: We examined the effects of adding glargine to metformin-sitagliptin (MS+G) or sitagliptin to metformin-glargine (MG+S) therapy in type 2 diabetic persons uncontrolled after 24-week MS or MG dual therapy. METHODS: Subjects with A1c≥7% on MS or MG treatment were respectively given glargine (0.2U/kg starting dose) or sitagliptin (100mg daily) for 12weeks. The primary endpoint was number of subjects attaining A1c goal defined as <7%. RESULTS: After receiving 24-week MS or MG dual therapy in the original EASIE Study, 42% (104/248) on MS and 68% (152/224) on MG attained A1c<7% (p<0.0001). The reduction in A1c was negatively associated with baseline fasting blood glucose (FBG) only in the MG group. Reduction in A1c was not related to baseline postprandial blood glucose (PPBG) in either the MG or MS group. Amongst 194 eligible patients, 57.7% (n=111) entered the 12-week extension trial [MS+G:74/131, 57.3%; MG+S:37/63, 58.7%) with 55 (51.9%) subjects attaining goal [MS+G:59.2%; MG+S:37.1%] at week 12. The final insulin dosage was similar in both groups [MS+G: 0.46U/kg; MG+S: 0.45U/kg] with a higher rate of hypoglycemia in the MG+S (6.5 events/patient-year) than the MS+G group (3.2 events/patient-year), although neither group had severe hypoglycemia. CONCLUSION: In metformin-treated type 2 diabetes patients, high fasting BG predicted greater A1c reductions with the addition of glargine, but not with sitagliptin. In subjects uncontrolled with 6-month dual therapy of MS or MG, 50% attained A1c<7% with triple therapy of MS+G or MG+S in 12weeks. The increased rate of hypoglycemia with MG+S (but not with MS+G) underlines the need to take measures to avoid the hypoglycemia.

Efficacy and safety of basal insulin glargine 12 and 24 weeks after initiation in persons with type 2 diabetes: a pooled analysis of data from treatment arms of 15 treat-to-target randomised controlled trials.

AIM: Evaluate early (0-12 weeks) and later (12-24 weeks) treatment outcomes in subjects with type 2 diabetes not achieving glycaemic control with oral antidiabetes drugs (OADs). METHODS: Selected data were pooled from 15 randomised, controlled treat-to-target (fasting plasma glucose < 100mg/dL [< 5.6 mmol/L]) trials adding insulin glargine to metformin, a sulphonylurea, or both. Glycaemic and hypoglycaemia parameters, insulin dose, and body weight at weeks 12 and 24 were assessed using individualised subject-level data. RESULTS: Data from 2837 subjects were analysed. HbA1c decreased from 8.8% (73 mmol/mol) at baseline by 1.4% (15 mmol/mol) at Week 12, and a further 0.2% (2 mmol/mol) at Week 24 in the pooled population. Similar reductions were observed across the different treatment groups. HbA1c < 7.0% (<53 mmol/mol) was reached by 34.8% of participants at Week 12 and an additional 24.3% by Week 24. Hypoglycaemia incidence and rates were similar during the early and continued treatment periods across all treatment combinations, but were markedly lower for insulin glargine plus metformin versus the other 2 regimens. CONCLUSIONS: Early and sustained glycaemic benefits with a low-risk of hypoglycaemia are observed after initiation of insulin glargine in a pooled type 2 diabetes cohort previously uncontrolled on OADs.

Reduced risk of hypoglycemia with once-daily glargine versus twice-daily NPH and number needed to harm with NPH to demonstrate the risk of one additional hypoglycemic event in type 2 diabetes: Evidence from a long-term controlled trial.

AIMS: This analysis evaluated HbA1c-adjusted hypoglycemia risk with glargine versus neutral protamine Hagedorn (NPH) over a 5-year study in patients with Type 2 diabetes mellitus (T2DM). Clinical significance was assessed using number needed to harm (NNH) to demonstrate the risk of one additional patient experiencing at least one hypoglycemic event. METHODS: Individual patient-level data for symptomatic documented hypoglycemia and HbA1c values from a 5-year randomized study comparing once-daily glargine (n=513) with twice-daily NPH (n=504) were analyzed. Symptomatic hypoglycemia was categorized according to concurrent self-monitoring blood glucose levels and need for assistance. Hypoglycemic events per patient-year as a function of HbA1c were fitted by negative binomial regression using treatment and HbA1c at endpoint as independent variables. An estimate of NNH was derived from logistic regression models. RESULTS: The cumulative number of symptomatic hypoglycemia events was consistently lower with glargine compared with NPH over 5years. Compared with twice-daily NPH, once-daily glargine treatment resulted in significantly lower adjusted odds ratios (OR) for all daytime hypoglycemia (OR 0.74; p=0.030) and any severe event (OR 0.64; p=0.035), representing a 26% and 36% reduction in the odds of daytime and severe hypoglycemia, respectively. Our model predicts that, if 25 patients were treated with NPH instead of glargine, then one additional patient would experience at least one severe hypoglycemic event. CONCLUSIONS: This analysis of long-term insulin treatment confirms findings from short-term studies and demonstrates that glargine provides sustained, clinically meaningful reductions in risk of hypoglycemia compared with NPH in patients with T2DM.

A Patient-level Analysis of Efficacy and Hypoglycaemia Outcomes Across Treat-to-target Trials with Insulin Glargine Added to Oral Antidiabetes Agents in People with Type 2 Diabetes.

Background: A better understanding of hypoglycaemia risk when insulin is used in combination with one or more oral antidiabetes agents may assist in the treatment decision-making process for the clinician and address concerns regarding hypoglycaemia when initiating or intensifying insulin therapy. The objective of this study was to analyse efficacy and hypoglycaemia outcomes in people with type 2 diabetes receiving insulin glargine (IG) with metformin (MET), sulphonylurea (SU) or MET+SU. Methods: Patient-level data were pooled from 15 randomised, treat-to-target trials (fasting plasma glucose [FPG] targets <5.6 mmol/l) with a duration >24 weeks. Efficacy outcomes included glycated haemoglobin (HbA1c), FPG and HbA1c target achievement. Overall hypoglycaemia events were assessed by a confirmed PG value of <3.9, <3.1 and <2.8 mmol/l or assistance required; daytime, nocturnal (00:01-05:59 AM); and severe (assistance required or with confirmed PG <2.0 mmol/l). Results: Overall, 2,837 IG patients were analysed, with either MET (634), SU (906) or MET+SU (1,297) as background oral antidiabetes agents. Endpoint HbA1c in IG+MET and IG+MET+SU-treated patients was significantly lower than in IG+SU-treated patients (adjusted difference -0.32 %; p=0.0001 and -0.33 %; p=0.0002, respectively). Fewer patients achieved endpoint HbA1c <7.0 % with IG+SU (32 %) versus IG+MET (57 %) or IG+MET+SU (49 %). IG+SU and IG+MET+SU led to significant increases in overall, daytime and nocturnal hypoglycaemia versus IG+MET; severe hypoglycaemia was rare. Weight gain was lowest in IG+MET patients (adjusted difference -1.51 kg versus IG+SU; p<0.0001; -0.78 kg versus IG+MET+SU; p=0.0037) despite higher insulin doses (0.51 U/kg versus 0.43 and 0.42 U/kg, respectively). Conclusions: Better glycaemic goal achievement and reduced risk of hypoglycaemia and weight gain were observed with IG+MET versus IG+SU and IG+MET+SU, albeit with an increased insulin dose requirement.

Meta-Analysis of Maternal and Neonatal Outcomes Associated with the Use of Insulin Glargine versus NPH Insulin during Pregnancy.

As glargine, an analog of human insulin, is increasingly used during pregnancy, a meta-analysis assessed its safety in this population. A systematic literature search identified studies of gestational or pregestational diabetes comparing use of insulin glargine with human NPH insulin, with at least 15 women in both arms. Data was extracted for maternal outcomes (weight at delivery, weight gain, 1st/3rd trimester HbA(1c), severe hypoglycemia, gestation/new-onset hypertension, preeclampsia, and cesarean section) and neonatal outcomes (congenital malformations, gestational age at delivery, birth weight, macrosomia, LGA, 5 minute Apgar score >7, NICU admissions, respiratory distress syndrome, neonatal hypoglycemia, and hyperbilirubinemia). Relative risk ratios and weighted mean differences were determined using a random effect model. Eight studies of women using glargine (331) or NPH (371) were analyzed. No significant differences in the efficacy and safety-related outcomes were found between glargine and NPH use during pregnancy.

Are patients with type 2 diabetes reluctant to start insulin therapy? An examination of the scope and underpinnings of psychological insulin resistance in a large, international population.

OBJECTIVE: To examine the scope and underpinnings of psychological insulin resistance (PIR) across eight Western nations, with special attention to the potential influence of beliefs about insulin and broader patient beliefs regarding medications and diabetes. METHODS: A total of 1400 subjects with insulin-naïve, type 2 diabetes across eight nations completed an online survey. The survey assessed willingness to start insulin, beliefs about insulin and current medications, and diabetes-related emotional distress. RESULTS: The majority of respondents were male (59.3%), mean age was 51.6 years and mean diabetes duration was 6.1 years. A total of 17.2% reported they would be unwilling to start insulin (the PIR group), while 34.7% were ambivalent and 48.1% indicated they would be willing to do so. Marked differences by country were apparent, with PIR ranging from 5.9% (Spain) to 37.3% (Italy). Both unwilling and ambivalent patients reported significantly more negative (p < 0.001; p < 0.05) and fewer positive beliefs (p < 0.001; p < 0.01) about starting insulin, more negative feelings about their current medications (p < 0.01, p < 0.001), and more diabetes-related distress (p < 0.001; p < 0.05) than willing patients. Unwilling patients also reported significantly more negative (p < 0.05) and fewer positive beliefs (p < 0.001) about starting insulin than ambivalent patients. CONCLUSION: These are the first data demonstrating the prevalence of PIR across Western nations. PIR is strongly linked to positive and negative insulin beliefs, and may also reflect a broader discomfort with medications and with diabetes in general. Of note, however, PIR is a marker of behavioral intent only; it is not known whether this predicts actual behavior at the time when insulin is prescribed. When addressing patients who are reluctant to initiate insulin therapy, clinicians may find it valuable to inquire about their beliefs about insulin and their current medications.

Do physicians understand Type 2 diabetes patients' perceptions of seriousness; the emotional impact and needs for care improvement? A cross-national survey.

OBJECTIVE: To explore across countries the extent to which physicians understand Type 2 diabetes patients' perceptions of seriousness, worries about complications, emotional distress, and needs for care improvement. METHODS: Cross-sectional data were collected in a multinational survey (SHARED). Type 2 diabetes patients (n=1609), general practitioners (n=818) and diabetes specialists (n=697) from eight countries were included. Data were gathered online and via telephone interviews. Responses from patients and professionals were compared using descriptive statistics and multilevel analyses. RESULTS: Patients generally perceived diabetes as a serious condition and reported moderate distress. Physicians tended to underestimate patients' perceived seriousness, while overestimating their level of distress. Physicians had difficulty estimating which diabetes complications concerned patients most, and what they needed to feel more confident about their diabetes. Patients did not wish for more consultation time, but rather active involvement, information and easy access to their physician. CONCLUSION: Results of this large survey highlight the importance of patient involvement and shared decision making. PRACTICE IMPLICATIONS: Further improvement of patient-provider communication as a basis for shared responsibilities and achieving optimal treatment outcomes is needed. With the growing numbers of diabetes patients worldwide, task delegation should be considered, in the framework of a multidisciplinary diabetes care model.

Clinical experience with insulin glargine in type 1 diabetes.

The Diabetes Control and Complications Trial (DCCT) demonstrated the importance of optimal glycemic control achieved through intensive insulin therapy in reducing the microvascular complications associated with type 1 diabetes. However, the DCCT, which was conducted prior to the availability of insulin analogs, also reported a significant increase in severe hypoglycemia with intensive versus conventional therapy. Insulin analogs were developed to aid patients in achieving better diabetes control by providing insulins with optimized pharmacokinetic and pharmacodynamic characteristics. Insulin glargine was the first long-acting insulin analog with a 24-h duration of action, offering once-daily injection, and has now been in clinical use for over 10 years. The authors performed a systematic search of EMBASE, MEDLINE, and Web of Science (Science Citation Index) to determine the efficacy of insulin glargine in type 1 diabetes in basal-bolus insulin regimens. Randomized controlled trials have demonstrated that glycemic control with insulin glargine is at least comparable to that with neutral protamine Hagedorn (NPH) insulin in adults and in children and adolescents, and with continuous subcutaneous insulin infusion in adults. However, these same trials show a significantly lower risk for hypoglycemia with insulin glargine compared with NPH insulin in adults.

Further improvement in postprandial glucose control with addition of exenatide or sitagliptin to combination therapy with insulin glargine and metformin: a proof-of-concept study.

OBJECTIVE: To assess the effect of a 4-week adjunctive therapy of exenatide (EXE) (5-10 microg b.i.d.) or sitagliptin (SITA) (100 mg once daily) in response to a standardized breakfast meal challenge in 48 men or women with type 2 diabetes receiving insulin glargine (GLAR) + metformin (MET). RESEARCH DESIGN AND METHODS: This was a single-center, randomized, open-label, active comparator-controlled study with a three-arm parallel group design, consisting of: screening, 4- to 8-week run-in period, 4-week treatment period, and follow-up. In all three groups, the GLAR dose was titrated according to an algorithm (fasting blood glucose

A 24-week, randomized, treat-to-target trial comparing initiation of insulin glargine once-daily with insulin detemir twice-daily in patients with type 2 diabetes inadequately controlled on oral glucose-lowering drugs.

OBJECTIVE: To determine whether glargine is noninferior to detemir regarding the percentage of patients reaching A1C <7% without symptomatic hypoglycemia

Rationale, design, and baseline data of the insulin glargine (Lantus) versus insulin detemir (Levemir) Treat-To-Target (L2T3) study: A multinational, randomized noninferiority trial of basal insulin initiation in type 2 diabetes.

OBJECTIVE: To discuss the design and baseline data of the Lantus (sanofi-aventis, Paris, France) versus Levemir (Novo Nordisk A/S, Bagsvaerd, Denmark) Treat-To-Target (L2T3) study, a multinational, randomized comparison between the basal insulin analogs insulin glargine and insulin detemir. METHODS: Insulin-naive subjects with type 2 diabetes suboptimally controlled on oral glucose-lowering drugs (OGLDs) (including at least metformin) were randomized to 24-week treatment with either insulin glargine once-daily or insulin detemir twice-daily, titrated to obtain fasting plasma glucose <100 mg/dL. The primary outcome was the percentage of subjects reaching hemoglobin A1c (HbA1c) <7% without symptomatic confirmed hypoglycemia. Important secondary outcomes were quality of life and treatment satisfaction, which were repeatedly assessed using validated questionnaires. Also, biomedical and psychological determinants of failure to reach HbA1c <7% were explored. RESULTS: Recruitment was completed in November 2007. The majority of the randomized population (n = 973) was white (77.8%) and used one other OGLD beside metformin (70.7%). Concerning patient-reported outcomes, approximately 20% of subjects reported no physical symptoms of fatigue or hyperglycemia before insulin initiation, and approximately 10% were maximally satisfied with their previous treatment. One-third of patients (29.9%) reported suboptimal well-being, and 9.3% had a score indicating depression. Better emotional well-being was significantly associated with lower diabetes symptom distress and higher treatment satisfaction (respectively, r = -0.56 and 0.41; P < 0.001). CONCLUSIONS: The L2T3 study will extend the evidence on both the efficacy and the effects on quality of life and treatment satisfaction of the long-acting insulin analogs glargine and detemir. Additionally, it will increase our understanding of the factors important to the (self-)management of type 2 diabetes patients starting insulin.