Low Rate Of Hypoglycaemia Research Articles

Lack of Health-Related Quality of Life and Patient-Centred Outcome Measures in Randomized Controlled Trials Conducted for Diabetes Pharmacotherapy: SGLT-2 Receptor Inhibitors as An Example.

Use of SGLT-2 receptor inhibitors has been associated with weight loss and a low rate of hypoglycemia in comparison to sulfonylureas. These factors may improve health-related quality of life for patients with diabetes. To systematically explore randomized controlled trials (RCTs) involving SGLT-2 receptor inhibitors that reported health-related quality of life changes. A systematic review of SGLT-2 receptor inhibitors clinical trials, limited to RCTs and English language, was conducted utilizing PubMed databases. One-hundred and eighteen RCTs were reviewed and 62 RCTs meeting the inclusion criteria were assessed. All 62 RCTs reported body mass index (BMI) changes and HgbA1c reduction. Measures of health-related quality-of-life (HRQoL) were reported in only 2 RCTs. Both studies illustrate improvement in HRQoL domains for SGLT-2 receptor inhibitors in comparison to the other arms in the RCTs. Only a small portion of RCTs involving SGLT-2 receptor inhibitors reported on HRQoL. Because of the potential for weight loss and hypoglycemia avoidance to improve HRQoL, future studies of SGLT-2 receptor inhibitors should measure and report on patient-centred outcomes such as HRQoL.

Hypoglycemia Rates After Restriction of High-Dose Glargine in Hospitalized Patients

Hypoglycemia remains one of the main challenges of insulin therapy. To reduce insulin-related hypoglycemia at our institution, we restricted inpatient ordering of high glargine doses (≥0.5 U/kg/day) to endocrine staff in May 2013. This retrospective cohort study assesses its effect on hypoglycemia and glycemic control within 48 hours of admission (ADM). We identified 692 adult patients hospitalized at Boston Medical Center who received glargine upon ADM from November 1, 2012 through April 30, 2013 as the pre-intervention group, and 651 adult patients admitted between November 1, 2013 and April 30, 2014 as the postintervention group. Demographics, medical history, home insulin regimen, concurrent oral diabetes medications or glucocorticoid administration, ADM serum creatinine, all blood glucose levels (BG) ≤48 hours of ADM, and hemoglobin A1c values ≤3 months were assessed. Hypoglycemia was defined as BG ≤70 mg/dL, and hyperglycemia as BG ≥200 mg/dL. Multivariable regression models assessed potential associations between covariates and incidence of hypoglycemia and average BG ≤48 hours of ADM. Demographics were similar between groups. Significantly less patients received high-dose glargine in the post-intervention group (5.2% vs. 0.3%, P<.001). Incidences of hypoglycemia were significantly lower in the postintervention group (20.9% vs. 17.8%, P<.001 per ADM; 3.4% vs. 2.3%, P = .001 per BG measurements [BGM]). Mean BG levels ≤48 hours of ADM and incidence of hyperglycemia were not significantly different. The adjusted incident rate ratio of hypoglycemia was 0.63 per ADM and 0.74 per BGM in the postintervention group compared to the pre-intervention group (P = .001 and P = .063, respectively). We found that implementation of a restriction on high doses of glargine resulted in lower rates of hypoglycemia without worsening glycemic control. ADM = admission BG = blood glucose BGM = blood glucose measurements BMC = Boston Medical Center BMI = body mass index EMR = electronic medical record HgbA1c = hemoglobin A1c IRR = incidence rate ratio NPH = neutral protamine Hagedorn TDD = total daily dose T2D = type 2 diabetes.

Use of healthcare resources and costs associated to the start of treatment with injectable drugs in patients with type 2 diabetes mellitus

ObjectivesThe main objective was to assess resource use and costs of starting treatment with insulin or injectable GLP-1 receptor analogs (GLP-1 RAs) in a Spanish population of patients with type 2 diabetes mellitus. Treatment adherence and persistence were also determined for both treatment groups. Patients and methodsA retrospective, non-interventional, observational study was conducted. Patients aged ≥20 years who started treatment with insulin or GLP-1 RAs in the 2010–2012 period were recruited. Use of healthcare resources was estimated to evaluate healthcare costs in these two groups of patients (medical visits, hospital stay, emergency visits, diagnostic or treatment requests, medication). Clinical information including body mass index (BMI, kg/m2), metabolic control (HbA1c), adherence, persistence, and complications hypoglycemia, and cardiovascular events (CVE) was collected. The follow-up period was 12 months. Only direct healthcare costs were considered. ResultsA total of 1301 patients with a mean age of 67.6 years (51.6% males) were recruited. Of these, 71.9% and 28.1% were on treatment with insulin and GLP-1 RA respectively. After one year of follow-up, patients treated with GLP-1 RAs were found less visits to primary care (8 vs. 11; p<0.001) and specialized care (1.0 vs. 1.8; p<0.001), hospital stays (0.3 vs. 0.7; p=0.030) and less visits to the emergency room (0.8 vs. 1.6; p<0.001). Patients treated with GLP-1 showed greater adherence (88.1% vs. 82.7%; p<0.001) and persistence (62.0% vs. 55.9%; p=0.046), and had less hypoglycemia episodes (13.4% vs. 18.7%; p=0.022), with similar metabolic control (HbA1c: 7.2% vs. 7.4%; p=0.049), BMI (29.1 vs. 30.9kg/m2), and CVE rate (9.1% vs. 11.5%; p=0.330) respectively. The mean corrected direct healthcare cost per patient was €1787 vs. €2005 (p=0.046.) ConclusionsPatients treated with GLP-1 RAs caused lower direct healthcare costs for the National Health System than patients treated with insulin. The results may be explained by greater treatment adherence and lower hypoglycemia rates in patients treated with GLP-1 RAs. Additional studies are needed to confirm these possibilities.

Consumo de recursos sanitarios y costes asociados al inicio del tratamiento con fármacos inyectables en pacientes con diabetes mellitus tipo 2

ObjectivesThe main objective was to assess resource use and costs of starting treatment with insulin or injectable GLP-1 receptor analogues (GLP-1 RAs) in a Spanish population of patients with type 2 diabetes mellitus. Treatment adherence and persistence were also determined for both treatment groups. Patients and methodsA retrospective, non-interventional, observational study was conducted. Patients aged ≥20 years who started treatment with insulin or GLP-1 RAs in the 2010-2012 period were recruited. Use of healthcare resources was estimated to evaluate healthcare costs in these two groups of patients (medical visits, hospital stay, emergency visits, diagnostic or treatment requests, medication). Clinical information including body mass index (BMI, kg/m2), metabolic control (HbA1c), adherence, persistence, and complications (hypoglycemia, and cardiovascular events (CVE) was collected. The follow-up period was 12 months. Only direct healthcare costs were considered. ResultsA total of 1301 patients with a mean age of 67.6 years (51.6% males) were recruited. Of these, 71.9% and 28.1% were on treatment with insulin and GLP-1 RA respectively. After one year of follow-up, patients treated with GLP-1 RAs were found less visits to primary care (8 vs. 11; P<.001) and specialized care (1.0 vs. 1.8; P<.001), hospital stays (0.3 vs. 0.7; P=.030) and less visits to the emergency room (0.8 vs. 1.6; P<.001). Patients treated with GLP-1 showed greater adherence (88.1% vs. 82.7%; P<.001) and persistence (62.0% vs. 55.9%; P=.046), and had less hypoglycemia episodes (13.4% vs. 18.7%; P=.022), with similar metabolic control (HbA1c: 7.2% vs. 7.4%; P=.049), BMI (29.1 vs. 30.9kg/m2), and CVE rate (9.1% vs. 11.5%; P=.330) respectively. The mean corrected direct healthcare cost per patient was €1787 vs. €2005 (P=.046.) ConclusionsPatients treated with GLP-1 RAs caused lower direct healthcare costs for the National Health System than patients treated with insulin. The results may be explained by greater treatment adherence and lower hypoglycemia rates in patients treated with GLP-1 RAs. Additional studies are needed to confirm these possibilities.

Comparison of efficacy and safety of two starting insulin regimens in non-Asian, Asian Indian, and East Asian patients with type 2 diabetes: a post hoc analysis of the PARADIGM study.

ObjectiveThe objective of this study was to explore the efficacy and safety of insulin lispro mix 25 (25% insulin lispro and 75% insulin lispro protamine suspension [LM25]) or insulin glargine plus insulin lispro (G+L) in insulin-naïve patients with type 2 diabetes from different racial/ethnic groups.MethodsThree subgroups from the PARADIGM study were analyzed post hoc: non-Asian (n=130), Asian Indian (n=106), and East Asian (n=89).ResultsAll subgroups recorded glycated hemoglobin (HbA1c) reductions: non-Asian (LM25, −2.07%; G+L, −2.05%), Asian Indian (LM25, −1.75%; G+L, −1.60%), and East Asian (LM25, −2.03%; G+L, −1.76%); end point HbA1c values were higher in Asian Indians and East Asians than in non-Asians. Fewer Asian Indians (LM25, 43.2%; G+L, 29.2%) and East Asians (LM25, 37.5%; G+L, 36.1%) reached HbA1c <7% versus non-Asians (LM25, 51.7%; G+L, 48.1%); differences were not significant (P=0.12 and P=0.06, respectively). The mean total daily insulin dose (U/kg) for non-Asians was 0.67 (LM25) and 0.61 (G+L), for Asian Indians was 0.91 (LM25) and 0.90 (G+L), and for East Asians was 0.53 (LM25) and 0.59 (G+L). The ratio of mealtime to total insulin dose in the G+L arm for non-Asians was 0.19±0.23, for Asian Indians was 0.33±0.25, and for East Asians was 0.34±0.27. Overall incidence (%) of hypoglycemia in non-Asians was 94.1 (LM25) and 91.8 (G+L), in Asian Indians was 90.4 (LM25) and 88.5 (G+L), and in East Asians was 69.8 (LM25) and 77.3 (G+L).ConclusionAsian Indians showed least improvement in glycemic HbA1c reduction despite greater insulin use. East Asians and non-Asians achieved similar HbA1c reduction in the LM25 arm with a lower rate of hypoglycemia. Asians required more mealtime insulin coverage than non-Asians. This study added important insight into the effect of ethnicity on insulin treatment outcomes in patients with type 2 diabetes.

Clinical use of the co-formulation of insulin degludec and insulin aspart.

To provide a review of the available data and practical use of insulin degludec with insulin aspart (IDegAsp). Premixed insulins provide basal and prandial glucose control; however, they have an intermediate-acting prandial insulin component and do not provide as effective basal coverage as true long-acting insulins, owing to the physicochemical incompatibility of their individual components, coupled with the inflexibility of adjustment. The molecular structure of the co-formulation of IDegAsp, a novel insulin preparation, allows these two molecules to coexist without affecting their individual pharmacodynamic profiles. Clinical evidence in phase 2/3 trials of IDegAsp efficacy and safety in type 1 and type 2 diabetes mellitus (T1DM and T2DM) have been assessed and summarised. In people with T2DM, once- and twice-daily dosing provides similar overall glycaemic control (HbA1c ) to current modern insulins, but with lower risk of nocturnal hypoglycaemia. In prior insulin users, glycaemic control was achieved with lower or equal insulin doses vs. other basal+meal-time or premix insulin regimens. In insulin-naïve patients with T2DM, IDegAsp can be started once or twice-daily, based on individual need. People switching from more than once-daily basal or premix insulin therapy can be converted unit-to-unit to once-daily IDegAsp, although this strategy should be assessed by the physician on an individual basis. IDegAsp offers physicians and people with T2DM a simpler insulin regimen than other available basal-bolus or premix-based insulin regimens, with stable daytime basal coverage, a lower rate of hypoglycaemia and some flexibility in injection timing compared with premix insulins.

Efficacy and safety of dulaglutide in the treatment of type 2 diabetes: a comprehensive review of the dulaglutide clinical data focusing on the AWARD phase 3 clinical trial program

Dulaglutide (DU) is a once weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA) approved for the treatment of type 2 diabetes mellitus (T2DM). Glycaemic efficacy and safety characteristics of dulaglutide have been assessed in six Phase 3 studies in the AWARD program. The objective of this review article is to summarize these results from the six completed AWARD studies. At the primary endpoint, in five of the six studies, once weekly dulaglutide 1.5mg was superior to the active comparator [exenatide, insulin glargine (two studies), metformin, and sitagliptin], with a greater proportion of patients reaching glycated hemoglobin A1c (HbA1c) targets of <7.0% (53.0mmol/mol) and ≤6.5% (47.5mmol/mol). Dulaglutide 1.5mg was non-inferior to liraglutide in AWARD-6. Once weekly dulaglutide 0.75mg was evaluated in five of these trials and demonstrated superiority to the active comparator in four of five AWARD studies (exenatide, glargine, metformin, and sitagliptin), and non-inferiority to glargine in the AWARD-2 study. Similar to other GLP-1 receptor agonists, treatment with dulaglutide was associated with weight loss or attenuation of weight gain and low rates of hypoglycaemia when used alone or with non-insulin-secretagogue therapy. The most frequently reported adverse events were gastrointestinal, including nausea, vomiting, and diarrhea. The incidence of dulaglutide antidrug antibody formation was 1-2.8% with rare injection site reactions. In conclusion, dulaglutide is an effective treatment for T2DM and has an acceptable tolerability and safety profile. Copyright © 2016 John Wiley & Sons, Ltd.

Severe hypoglycemia in the Look AHEAD Trial

ObjectiveThe Look AHEAD trial was a multi-center, randomized controlled trial, to determine whether weight loss reduces cardiovascular morbidity and mortality in overweight individuals with type 2 diabetes. The objective of this study was to evaluate the incidence of severe hypoglycemia in patients enrolled in Look AHEAD.Research Design and Methods5,145 subjects were randomized to diabetes support and education (DSE) or intensive lifestyle intervention (ILI). Instances of severe hypoglycemia were recorded. Regression analysis was used to compare the development of severe hypoglycemia between groups. ResultsOver the entire study, the severe hypoglycemia rate was not different between ILI and DSE groups (0.49 ILI, 0.51 DSE/100 person–years, rate ratio=1.12, p=0.41), but was greater in ILI during year 1 (p=0.008 for year by intervention interaction). During follow-up, severe hypoglycemia risk was higher with insulin, sulfonylurea or glitinide use at baseline (p<0.0001). The intervention effect differed by post-randomization insulin use (ILI to DSE HR=1.45 in insulin users versus HR=0.71 in non-users, p=0.009). Insulin use reduced by 3% in ILI in year 1. Compared to DSE, ILI participants in the lower 50% of weight loss in year 1 had similar percent insulin use and incident hypoglycemia, but ILI participants in the upper 50% of weight loss had lower percent insulin use and incident hypoglycemia. ConclusionsReduction in insulin is necessary during intensive weight loss to avoid episodes of hypoglycemia. Although limited by self-reported evaluation of hypoglycemia, greater weight loss in ILI during year 1 was associated with reduced insulin use and lower rates of hypoglycemia later in the trial.

Lower rates of hypoglycemia during maintenance treatment with insulin degludec/insulin aspart versus biphasic insulin aspart 30: a combined analysis of two Phase 3a studies in type 2 diabetes.

Insulin degludec/insulin aspart (IDegAsp) is a soluble coformulation of the basal analog insulin degludec and the rapid-acting prandial insulin aspart in a single injection. The present combined analysis of two Phase 3a trials compared the incidence of hypoglycemia in participants treated twice daily with IDegAsp or biphasic insulin aspart 30 (BIAsp 30). Hypoglycemia data were analyzed from two similarly designed randomized controlled open-label treat-to-target Phase 3a clinical trials of adults with type 2 diabetes (T2D). Participants were treated twice daily with IDegAsp or BIAsp 30, with breakfast and their main evening meal. Over 26 weeks, the rates of overall confirmed, nocturnal confirmed and severe hypoglycemic events were 19%, 57%, and 39% lower, respectively, with IDegAsp (n = 504) than BIAsp 30 (n = 364); estimated rate ratios were 0.81 (95% confidence interval [CI] 0.67, 0.98; P = 0.0341), 0.43 (95% CI 0.31, 0.59; P = 0.0001), and 0.61 (95% CI 0.26, 1.45; P = NS). The between-treatment differences were more pronounced during the maintenance period (≥16 weeks); compared with BIAsp 30, rates of overall confirmed, nocturnal confirmed and severe hypoglycemic events with IDegAsp were 0.69 (95% CI 0.55, 0.87; -31%; P = 0.0015); 0.38 (95% CI 0.25, 0.58; -62%; P < 0.0001), and 0.16 (95% CI 0.04, 0.59; -84%; P = 0.0061), respectively. Compared with BIAsp 30 twice daily, IDegAsp twice daily provided similar improvements in glycemic control with a lower risk of hypoglycemia, particularly nocturnal hypoglycemia, in subjects with T2D previously treated with insulin.

Sodium-glucose cotransporter-2 inhibitor combination therapy to optimize glycemic control and tolerability in patients with type 2 diabetes: focus on dapagliflozin-metformin.

In type 2 diabetes (T2D), early combination therapy using agents that target a number of the underlying pathophysiologic defects contributing to hyperglycemia may improve patient outcomes. For many patients, the combination of metformin with a sodium–glucose cotransporter-2 (SGLT-2) inhibitor may be a good option because these agents have complementary mechanisms of action, neutral-to-positive effects on body weight, and a low risk of hypoglycemia. This review focuses on the combination of metformin with dapagliflozin, a member of the SGLT-2 inhibitor class of antidiabetes agents. In clinical trials, the combination of dapagliflozin with metformin produced significant and sustained reductions in glycated hemoglobin and body weight in a broad range of adult patients with T2D, including those initiating pharmacotherapy and those with more advanced disease. These reductions were accompanied by modest decreases in blood pressure. Dapagliflozin as add-on therapy to metformin was well tolerated and associated with low rates of hypoglycemia. Genital infections and, in some studies, urinary tract infections were more frequent with dapagliflozin than with placebo. Early combination therapy with dapagliflozin and metformin may be a safe and appropriate treatment option that enables patients with T2D to achieve individualized glycemic goals as either initial combination therapy in treatment-naïve patients or as dapagliflozin add-on in patients inadequately controlled with metformin therapy.

Pharmacokinetic, pharmacodynamic and clinical evaluation of saxagliptin in type 2 diabetes

ABSTRACTIntroduction: Dipeptide peptidase-4 (DPP-4) inhibitors such as saxagliptin are established and efficacious oral therapies in the management of type 2 diabetes. These agents have the potential to confer significant benefits in glycemic control without the risk of weight gain and hypoglycemia, which may be associated with other medications used to treat type 2 diabetes.Areas covered: This review examines the pharmacokinetics, efficacy and tolerability of saxagliptin for the management of type 2 diabetes.Expert opinion: Saxagliptin is routinely used in the management of type 2 diabetes as monotherapy, and in combination with other oral agents and insulin. Robust clinical trials have shown consistent improvements in glycated hemoglobin, fasting and postprandial glucose levels, with few adverse effects. The agent is well tolerated with low rates of hypoglycemia in the absence of insulin or sulphonylurea therapy.

Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors.

Over the last few years, incretin‐based therapies have emerged as important agents in the treatment of type 2 diabetes (T2D). These agents exert their effect via the incretin system, specifically targeting the receptor for the incretin hormone glucagon‐like peptide 1 (GLP‐1), which is partly responsible for augmenting glucose‐dependent insulin secretion in response to nutrient intake (the ‘incretin effect’). In patients with T2D, pharmacological doses/concentrations of GLP‐1 can compensate for the inability of diabetic β cells to respond to the main incretin hormone glucose‐dependent insulinotropic polypeptide, and this is therefore a suitable parent compound for incretin‐based glucose‐lowering medications. Two classes of incretin‐based therapies are available: GLP‐1 receptor agonists (GLP‐1RAs) and dipeptidyl peptidase‐4 (DPP‐4) inhibitors. GLP‐1RAs promote GLP‐1 receptor (GLP‐1R) signalling by providing GLP‐1R stimulation through ‘incretin mimetics’ circulating at pharmacological concentrations, whereas DPP‐4 inhibitors prevent the degradation of endogenously released GLP‐1. Both agents produce reductions in plasma glucose and, as a result of their glucose‐dependent mode of action, this is associated with low rates of hypoglycaemia; however, there are distinct modes of action resulting in differing efficacy and tolerability profiles. Furthermore, as their actions are not restricted to stimulating insulin secretion, these agents have also been associated with additional non‐glycaemic benefits such as weight loss, improvements in β‐cell function and cardiovascular risk markers. These attributes have made incretin therapies attractive treatments for the management of T2D and have presented physicians with an opportunity to tailor treatment plans. This review endeavours to outline the commonalities and differences among incretin‐based therapies and to provide guidance regarding agents most suitable for treating T2D in individual patients.

Insulin degludec/liraglutide (IDegLira) for the treatment of type 2 diabetes

The progressive nature of type 2 diabetes necessitates that treatment is intensified as the disease advances. Several studies have shown that basal insulin and glucagon-like peptide-1 receptor agonists (GLP-1RAs) can be used in combination to successfully improve glycemic control and this combination is increasingly being considered as an alternative to intensification with prandial insulin. Insulin degludec/liraglutide (IDegLira) is the first fixed-ratio combination of a basal insulin and a GLP-1RA in a single formulation. Here we consider the benefits and potential limitations of such a combination, focusing on the unique modes of action of insulin degludec and the once-daily GLP-1RA liraglutide. IDegLira offers an efficacious combination therapy (mean end-of-trial HbA1c was 6.4–6.9% across the five completed Phase 3 trials), which was well-tolerated in clinical trials. The complementary modes of action resulted in a low rate of hypoglycemia and no weight gain in insulin-treated patients. As a once-daily injection with effects on both fasting and post prandial hyperglycemia, IDegLira has the potential to help many patients reach glycemic target (60–81% of patients achieved HbA1c <7% in clinical trials).

IDegLira Versus Alternative Intensification Strategies in Patients with Type 2 Diabetes Inadequately Controlled on Basal Insulin Therapy.

IntroductionIDegLira is a once-daily combination of insulin degludec (IDeg) and liraglutide. Trials directly comparing IDegLira with alternative strategies for intensifying basal insulin are ongoing. While awaiting results, this analysis compared indirectly how different strategies affected glycated hemoglobin (HbA1c) and other outcomes.MethodsA pooled analysis of five completed Novo Nordisk randomized clinical trials in patients with type 2 diabetes inadequately controlled on basal insulin was used to compare indirectly IDegLira (N = 199) with: addition of liraglutide to basal insulin (N = 225) [glucagon-like peptide-1 receptor agonist (GLP-1RA) add-on strategy]; basal–bolus (BB) insulin [insulin glargine (IGlar) + insulin aspart] (N = 56); or up-titration of IGlar (N = 329). A supplementary analysis was performed with the BB arm including patients who received IGlar or IDeg as basal insulin in the relevant trial (N = 210). All trials had comparable inclusion/exclusion criteria and baseline characteristics. Individual patient-level data were analyzed using multivariable statistical models with potential baseline heterogeneity accounted for using explanatory variables.ResultsAt end of study, differences between IDegLira and BB or up-titrated IGlar, respectively, were as follows: reduction in HbA1c −0.30%, 95% confidence interval (–0.58; −0.01) and −0.65% (−0.83; −0.47); change in body weight −6.89 kg (−7.92; −5.86) and −4.04 kg (−4.69; −3.40) all in favor of IDegLira. Confirmed hypoglycemia rate was 122.8 (90.7; 166.1), 1060.8 (680.2; 1654.4), and 286.1 (231.1; 354.1) events/100 patient-years for IDegLira, BB, and up-titrated IGlar, respectively. Odds ratios for achieving HbA1c <7.0%, <7.0% without hypoglycemia, and <7.0% without hypoglycemia and no weight gain were greater with IDegLira versus up-titrated IGlar. The supplementary analysis yielded similar results to the main analysis. Results with IDegLira were similar to those for the ‘GLP-1RA add-on’ arm.ConclusionThese results suggest that IDegLira may be more effective, with lower hypoglycemia rates and less weight gain, than up-titrated basal insulin or BB in patients uncontrolled on basal insulin.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-015-0142-y) contains supplementary material, which is available to authorized users.

Efficacy and safety of once-weekly GLP-1 receptor agonist albiglutide (HARMONY 2): 52 week primary endpoint results from a randomised, placebo-controlled trial in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise.

Aims/hypothesisAdditional safe and effective therapies for type 2 diabetes are needed, especially ones that do not cause weight gain and have a low risk of hypoglycaemia. The present study evaluated albiglutide as monotherapy.MethodsIn this placebo-controlled study, 309 patients (aged ≥18 years) with type 2 diabetes inadequately controlled by diet and exercise and who were not using a glucose-lowering agent (HbA1c 7.0–10.0% [53.00–85.79 mmol/mol], body mass index 20–45 kg/m2, and fasting C-peptide ≥0.26 nmol/l) were randomised (1:1:1 on a fixed randomisation schedule using an interactive voice response system) to receive once-weekly albiglutide 30 mg (n = 102) or 50 mg (n = 102) or matching placebo (n = 105). The study treatments were blinded to both patients and study personnel. All study data were collected at individual patient clinic visits. The primary efficacy endpoint was change in HbA1c from baseline to week 52. The primary analysis was applied to the intent-to-treat population. Additional efficacy and safety endpoints were assessed.ResultsAt week 52, both albiglutide 30 mg and 50 mg were superior to placebo in reducing HbA1c. The least-squares means treatment difference from placebo was −0.84% (95% CI −1.11%, −0.58%; p < 0.0001) with albiglutide 30 mg and −1.04% (−1.31%, −0.77%; p < 0.0001) with albiglutide 50 mg. Injection-site reactions were reported more frequently with albiglutide (30 mg: 17.8%; 50 mg: 22.2%) than with placebo (9.9%). Other commonly reported adverse events included nausea, diarrhoea, vomiting and hypoglycaemia; the incidences of these were generally similar across treatment groups.Conclusions/interpretationAlbiglutide is safe and effective as monotherapy and significantly lowered HbA1c levels over 52 weeks, did not cause weight gain, and had good gastrointestinal tolerability and a low rate of hypoglycaemia compared with placebo.Trial registration ClinicalTrials.gov NCT00849017Funding This study was sponsored by GlaxoSmithKline.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-015-3795-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

How much is too much? Outcomes in patients using high-dose insulin glargine.

SummaryBackground and objectivesMany patients with type 2 diabetes mellitus (T2DM) do not achieve glycaemic control targets on basal insulin regimens. This analysis investigated characteristics, clinical outcomes and impact of concomitant oral antidiabetes drugs (OADs) in patients with T2DM treated with high‐dose insulin glargine.MethodsPatient‐level data were pooled from 15 randomised, treat‐to‐target trials in patients with T2DM treated with insulin glargine ± OADs for ≥ 24 weeks. Data were stratified according to whether patients exceeded three insulin dose cut‐off levels (> 0.5, > 0.7 and > 1.0 IU/kg). End‐points included glycated haemoglobin A1c (A1C), fasting plasma glucose, body weight, and overall, nocturnal and severe hypoglycaemia.ResultsData from 2837 insulin‐naïve patients were analysed. Patients with insulin titrated beyond the three doses investigated had significantly higher baseline A1C levels and were younger, with shorter diabetes duration than those at/below cut‐offs (p < 0.05 for all cut‐offs); they also had greater weight gain (p < 0.001 for the > 0.5 and > 0.7 IU/kg cut‐offs) than those who did not exceed the cut‐offs, regardless of concomitant OAD. Patients on concomitant metformin alone had higher insulin doses at Week 24, but achieved greater reductions in A1C, less weight gain and lower hypoglycaemia rates than patients on a concomitant sulfonylurea or metformin plus a sulfonylurea, regardless of whether cut‐offs were exceeded.ConclusionIn patients with T2DM, increasing basal insulin doses above 0.5 IU/kg may not improve glycaemic control; treatment strategies targeting postprandial glucose control should be considered for such patients.

An evaluation of the safety and efficacy of a variable rate intravenous insulin infusion in the management of hyperglycaemia in acute coronary syndrome: experience of the TITAN-ACS

Aim: To assess the safety and efficacy of a variable rate intravenous insulin infusion to lower blood glucose (BG) in patients presenting with acute coronary syndrome and hyperglycaemia. Methods: We evaluated the response over 24 hours of a variable rate insulin infusion with 5% dextrose and potassium chloride (40 mEq/L), to control hyperglycaemia in 776 patients with an admission BG ≥10 mmol/L in 36 UK hospitals. Patients had either ST segment elevation or non-ST segment elevation myocardial infarction and the study included both patients with or without a diagnosis of diabetes. We measured blood glucose, initially hourly, and serum potassium at admission, at 24 hours and at the time of major arrhythmias. We measured survival to 30 days. Results: Median admission BG was 14.3 mmol/L (interquartile range 11.7, 18.1). At 6 hours BG was 8.0 mmol/L (6.2, 10.8), and at 20-24 hours it was 8.3 mmol/L (6.5, 11.0). Hypokalaemia due to the infusion was not observed. Hypoglycaemia (BG 10.8 mmol/L at 6 hours; adjusted odds ratio 1.82, p=0.011. Conclusions: This insulin regimen was safe and effective with low rates of hypoglycaemia and no excess mortality in the hypoglycaemic subgroup. Further adjustments are required for those in the lowest and highest quartiles of weight.

Enteral Nutrition(EN) With Supplemental Parenteral Nutrition(SPN) in Critically Ill Patients in Northeastern China: A Randomized Controlled Clinical Trial

Introduction: Gastrointestinal function plays an important role in the treatment of critically ill. Even its dysfunction is known as a promoter of MODS. Although EN is recommended for patients in the ICU, many patients have gastrointestinal dysfunction so use EN simply can not achieve nutritional goals and maybe it will lead to negative outcomes. We assessed whether patients who had been achieved nutritional goals for seven days by EN plus SPN in northeastern China could optimise clinical outcome. Methods: This RCT was undertaken in multiple centres in Northeastern China. There was a total of 335 patients who were expected to stay and to survive for longer than 7 days meanwhile their nutrition risk screening(NRS) scores were more than 3. Age, gender, APACHE II score or LIFE score(day 1) were no statistically significant differences betweem both group. They were randomly distributed 167 to SPN and 168 to EN. 45 patients discontinued before the study end. We respectively set targets as 25 and 30 kcal per kg of ideal bodyweight a day for women and men. The patients in EN got the nutrient just in nutrition liquid diet(NLD) and the other team used NLD 20ml/h plus SPN simultaneously. The trial ceased at day 8 and measured until day 28. Results: 87 patients in EN can achieve targets energy by EN and 80 patients(47.9%) came out gastric retention(GR) and fail to targets energy. 53(31.7%) in SPN had GR(P < 0.05), plus PN and all were up to standard. 18(22.5%) patients had GR appered hypoglycemia, 12(7.2%) in SPN had hypoglycemia(p=0.001). EN had GR and SPN their respective rates of 28 days mortality had statistically significant differences (P < 0.05). Conclusion: EN plus SPN means patients can achieve the targets of energy as soon as possible. The patients have lower rate of hypoglycemia, lower 28 days mortality and higher adaptation campared with EN had GR. This way could be better in nutrition therapy for people with high NRS scores in Northeastern China.

Patients Achieving Good Glycemic Control (HBA1c

Meta-analysis to compare hypoglycemia rates of basal insulin degludec (IDeg) with insulin glargine (IGlar) in patients with diabetes achieving good glycemic control (hemoglobin A1c [HbA1c] <7% at end of trial). In a preplanned meta-analysis, patient data from 7 randomized, treat-to-target, 26- or 52-week trials in patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) who administered IDeg (n = 2,899) or IGlar (n = 1,431) once daily were analyzed. Using a negative binomial regression model, this meta-analysis compared hypoglycemia rates in patients achieving HbA1c <7% at end of trial with IDeg (n = 1,347) and IGlar (n = 697). In all trials, IDeg was noninferior to IGlar in HbA1c reduction from baseline. At end of trial, 2,044 patients (T2DM, n = 1,661; T1DM, n = 383) achieved HbA1c <7%. The overall confirmed hypoglycemia rate, defined as plasma glucose <56 mg/dL or severe hypoglycemia if requiring assistance, was significantly lower with IDeg versus IGlar (estimated rate ratio [ERR] IDeg:IGlar, 0.86; 95% confidence interval [CI], 0.76 to 0.98). The nocturnal confirmed hypoglycemia rate, defined as occurring between midnight and 6:00 am, was significantly lower with IDeg (ERR, 0.63; 95% CI, 0.52 to 0.77). In the maintenance period (16 weeks onward when average insulin dose and glycemic levels stabilized), the overall confirmed hypoglycemia rate was significantly lower (ERR, 0.79; 95% CI, 0.68 to 0.92) and the nocturnal confirmed hypoglycemia rate was significantly lower (ERR, 0.57; 95% CI, 0.45 to 0.72) with IDeg versus IGlar. Patients with T1DM and T2DM achieved HbA1c <7% with significantly lower rates of overall and nocturnal confirmed hypoglycemia with IDeg versus IGlar. The lower hypoglycemia rate with IDeg was more pronounced in the maintenance period.

Combination therapy with insulin glargine plus metformin but not insulin glargine plus sulfonylurea provides similar glycemic control to triple oral combination therapy in patients with type 2 diabetes uncontrolled with dual oral agent therapy

AimsEvaluate substituting insulin glargine (GLAR) for a thiazolidinedione (TZD) versus adding a third oral antidiabetes drug (OAD) in patients with uncontrolled type 2 diabetes mellitus (T2DM) on TZD+metformin or TZD+sulfonylurea. MethodsIn this multicenter, open-label study, 337 T2DM patients with a glycated hemoglobin A1c (A1C) of 7.5–12.0% despite≥3months of treatment with a TZD plus metformin or a sulfonylurea were randomized to a third OAD (3OAD; metformin or glyburide) or GLAR+1 OAD (metformin or sulfonylurea) with TZD cessation, titrated to a fasting blood glucose≤94mg/dL. ResultsSubstitution of GLAR for a TZD led to an adjusted mean A1C change from baseline of−1.66% versus−1.86% in the 3OAD arm (adjusted mean difference 0.20 [95% confidence interval, − 0.11, 0.51], not meeting the noninferiority criteria). This difference was driven by the GLAR+sulfonylurea stratum. GLAR+metformin was as effective as 3OAD in achieving glycemic control but with greater improvements in lipid parameters, less weight gain, and lower hypoglycemia rates. ConclusionsThese findings favor substitution of GLAR for a TZD in T2DM patients not controlled on TZD+metformin. GLAR+sulfonylurea was less effective at lowering A1C than 3OAD and not associated with the benefits observed with GLAR+metformin.