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

AbstractAimsThis 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.MethodsIndividual 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.ResultsThe 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.ConclusionsThis 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

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 HbA1c, 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

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

Q3Q1Aims: Demonstrate superiority of insulin glargine (±glulisine) strategy versus premixed insulin strategy for percentage of patients reaching HbA1c b7% (b53 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) b7 mmol/L at week 12. IS was stopped with any second injection. Insulin titration targeted FBG ≤5.6 mmol/L. Results: Modifiedintent-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-specifiedmargin: 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.N/

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

Q3Q1Aim 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 (0.2 U/kg starting dose) or sitagliptin (100 mg daily) for 12 weeks. 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: 0.46 U/kg; MG + S: 0.45 U/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 12 weeks. The increased rate of hypoglycemia with MG + S (but not with MS + G) underlines the need to take measures to avoid the hypoglycemia

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. Copyright © 2015 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved

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 A1c (HbA1c) of 7–11%, diagnosis of type 2 diabetes for at least 6 months, and body-mass index of 25–45 kg/m2 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 HbA1c 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 HbA1c 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

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 (R) (sanofi-aventis, Paris, France) versus Levemir (R) (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, similar to 20% of subjects reported no physical symptoms of fatigue or hyperglycemia before insulin initiation, and similar to 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 insuli

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

AbstractAimWe 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.MethodsSubjects 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%.ResultsAfter 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.ConclusionIn 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