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Aim: To compare the addition of weekly dulaglutide vs the addition of placebo to titrated glargine in patients with type 2 diabetes (T2D) with sub-optimum glycated haemoglobin (HbA1c) concentration., Materials and Methods: Patients (N = 300) from this phase III, double-blind, parallel-arm, placebo-controlled study were randomized to weekly subcutaneous injections of dulaglutide 1.5 mg or placebo with titrated daily glargine (mean ± standard deviation baseline dose: 39 ± 22 U), with or without metformin (≥1500 mg/d). The primary endpoint was superiority of dulaglutide/glargine to placebo/glargine with regard to change from baseline in HbA1c level at 28 weeks., Results: Least squares (LS) mean ± standard error (s.e.) HbA1c changes from baseline were -1.44 ± 0.09% (-15.74 ± 0.98 mmol/mol) with dulaglutide/glargine and -0.67 ± 0.09% (-7.32 ± 0.98 mmol/mol) with placebo/glargine at 28 weeks (LS mean difference [95% confidence interval] -0.77% [-0.97, -0.56]; P < .001). Body weight decreased with dulaglutide/glargine and increased with placebo/glargine (LS mean difference: -2.41 ± 0.39 kg; P < .001). Increases from baseline in mean glargine dose were significantly smaller with dulaglutide/glargine vs placebo/glargine (13 ± 2 U [0.1 ± 0.02 U/kg] vs 26 ± 2 U [0.3 ± 0.02 U/kg], respectively; P < .001; LS mean ± s.e. final dose: dulaglutide/glargine, 51 ± 2 U; placebo/glargine, 65 ± 2 U). The hypoglycaemia rate (≤3.9 mmol/L threshold) was 7.69 ± 15.15 and 8.56 ± 16.13 events/patient/year, respectively (P = .488). One episode of severe hypoglycaemia occurred in the dulaglutide/glargine group. Common gastrointestinal adverse events with dulaglutide were nausea (12.0%), diarrhoea (11.3%) and vomiting (6.0%)., Conclusions: Weekly dulaglutide 1.5 mg added to basal insulin is an efficacious and well tolerated treatment option for patients with T2D., (© 2017 John Wiley & Sons Ltd.)

Background: In Phase 2/3 studies of basal insulin peglispro (BIL) compared to insulin glargine, patients with type 1 or type 2 diabetes previously treated with insulin and randomized to BIL had an increase in serum triglycerides (TGs). To further understand lipoprotein changes, a lipid substudy which included liver fat content was designed to assess relationships among the measured variables for each diabetes cohort and compare the hepato-preferential insulin BIL to glargine., Methods: In three cohorts of patients with diabetes (type 1, type 2 insulin naïve, and type 2 previously on insulin; n = 652), liver fat content (LFC) was determined by magnetic resonance imaging (MRI) and blood lipids were analyzed by nuclear magnetic resonance (NMR) spectroscopy at baseline, 26 and 52 weeks of treatment. Apolipoproteins, adiponectin, and other lipid parameters were also measured. Descriptive statistics were done, as well as correlation analyses to look for relationships among LFC and lipoproteins or other lipid measures., Results: In patients with type 1 diabetes treated with BIL, but not glargine, small LDL and medium and large VLDL subclass concentrations increased from baseline. In patients with type 2 diabetes previously on insulin and treated with BIL, large VLDL concentration increased from baseline. In insulin naïve patients with type 2 diabetes treated with BIL, there were very few changes, while in those treated with glargine, small LDL and large VLDL decreased from baseline. Baseline LFC correlated significantly in one or more cohorts with baseline large VLDL, small LDL, VLDL size, and Apo C3. Changes in LFC by treatment showed generally weak correlations with lipoprotein changes, except for positive correlations with large VLDL and VLDL size. Adiponectin was higher in patients with type 1 diabetes compared to patients with type 2 diabetes, but decreased with treatment with both BIL and glargine., Conclusions: The lipoprotein changes were in line with the observed changes in serum TGs; i.e., the cohorts experiencing increased TGs and LFC with BIL treatment had decreased LDL size and increased VLDL size. These data and analyses add to the currently available information on the metabolic effects of insulins in a very carefully characterized cohort of patients with diabetes. Clinicaltrials.gov registration numbers and dates NCT01481779 (2011), NCT01435616 (2011), NCT01454284 (2011), NCT01582451 (2012).

Aims: To evaluate factors associated with reaching or not reaching target glycated haemoglobin (HbA 1c ) levels by analysing the respective contributions of fasting hyperglycaemia (FHG), also referred to as basal hyperglycaemia, vs postprandial hyperglycaemia (PHG) before and after initiation of a basal or premixed insulin regimen in patients with type 2 diabetes., Methods: This post-hoc analysis of insulin-naïve patients in the DURABLE study randomised to receive either insulin glargine or insulin lispro mix 25 evaluated the percentages of patients achieving a target HbA 1c of <7.0% (<53mmol/mol) per baseline HbA 1c quartiles, and the effect of each insulin regimen on the relative contributions of PHG and FHG to overall hyperglycaemia., Results: Patients had comparable demographic characteristics and similar HbA 1c and FHG values at baseline in each HbA 1c quartile regardless of whether they reached the target HbA 1c . The higher the HbA 1c quartile, the greater was the decrease in HbA 1c , but also the smaller the percentage of patients achieving the target HbA 1c . HbA 1c and FHG decreased more in patients reaching the target, resulting in significantly lower values at endpoint in all baseline HbA 1c quartiles with either insulin treatment. Patients not achieving the target HbA 1c had slightly higher insulin doses, but lower total hypoglycaemia rates., Conclusion: Smaller decreases in FHG were associated with not reaching the target HbA 1c , suggesting a need to increase basal or premixed insulin doses to achieve targeted fasting plasma glucose and improve patient response before introducing more intensive prandial insulin regimens., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Introduction: Increasing emphasis is being placed on insulin use among patients with type 2 diabetes mellitus (T2DM). Basal-bolus (BB) therapy is regarded as the gold standard, but a high frequency of injections and the general complexity of this therapy are seen as barriers in real-world practice. Here we describe the characteristics and treatment patterns of patients with T2DM receiving BB in the UK, with specific focus on those switching to a simplified regimen of premixed insulin., Methods: Patients with T2DM receiving BB from 1 January 2005 were identified from the Clinical Practice Research Datalink. Characteristics were described at treatment initiation or on 1 January 2005, and treatment patterns were assessed at 12 months of follow-up. Clinical factors were compared in two groups of patients who while receiving BB had one haemoglobin A1c (HbA1c) measurement of ≥53 mmol/mol (7.0%) and remained either on BB or switched to a premixed insulin regimen., Results: Study criteria were met by 12,060 subjects (mean age 59 years; duration diabetes 12.4 years). The mean HbA1c concentration was 76 mmol/mol (9.1% of patients), and 84.0% of patients were overweight. At 12 months of follow-up, 74.5% of the patients who had started BB remained on it. While on BB, 8835 patients had a HbA1c measurement of ≥53 mmol/mol (7.0% of all patients); of these, 95.9% remained on BB and 4.1% switched to premixed insulin. Mean HbA1c levels were consistently higher for patients who switched to premixed insulin than for those who remained on BB, but the levels remained relatively unchanged over time., Conclusion: A large proportion of patients receiving insulin did not achieve good glycaemic control in clinical practice. A small subset with higher comorbidities and HbA1c levels switched to a simplified regimen. Little evidence was found that type of insulin therapy was associated with meaningful changes in key clinical factors over time., Funding: Eli Lilly and company.

Basal insulin peglispro (BIL) is a novel basal insulin with hepato-preferential action resulting from reduced peripheral effects. This report provides an integrated summary of lipid changes at 26 weeks with BIL and comparator insulins (glargine, NPH) from phase III studies in type 1 diabetes (T1D), insulin-naïve patients with type 2 diabetes (T2D), patients with T2D on basal insulin only and patients with T2D on basal-bolus therapy. BIL treatment had little effect on HDL cholesterol and LDL cholesterol in all patients. The effect of both BIL and glargine treatment on triglycerides (TG) depended on whether patients had been previously treated with insulin. When BIL replaced conventional insulin glargine or NPH treatments, increases in TG levels were observed. When BIL or comparator insulins were given for 26 weeks to insulin-naïve patients with T2D, TG levels were unchanged from baseline with BIL but decreased with either glargine or NPH. The decreased peripheral action of BIL may reduce suppression of lipolysis in peripheral adipose tissue resulting in increased free fatty acid delivery to the liver and, hence, increased hepatic TG synthesis and secretion., (© 2016 John Wiley & Sons Ltd.)

Objective: To evaluate the efficacy and safety of basal insulin peglispro (BIL) versus insulin glargine in patients with type 2 diabetes (hemoglobin A1c [HbA1c] ≤9% [75 mmol/mol]) treated with basal insulin alone or with three or fewer oral antihyperglycemic medications., Research Design and Methods: This 52-week, open-label, treat-to-target study randomized patients (mean HbA1c 7.42% [57.6 mmol/mol]) to BIL (n = 307) or glargine (n = 159). The primary end point was change from baseline HbA1c to 26 weeks (0.4% [4.4 mmol/mol] noninferiority margin)., Results: At 26 weeks, reduction in HbA1c was superior with BIL versus glargine (-0.82% [-8.9 mmol/mol] vs. -0.29% [-3.2 mmol/mol]; least squares mean difference -0.52%, 95% CI -0.67 to -0.38 [-5.7 mmol/mol, 95% CI -7.3 to -4.2; P < 0.001); greater reduction in HbA1c with BIL was maintained at 52 weeks. More BIL patients achieved HbA1c <7% (53 mmol/mol) at weeks 26 and 52 (P < 0.001). With BIL versus glargine, nocturnal hypoglycemia rate was 60% lower, more patients achieved HbA1c <7% (53 mmol/mol) without nocturnal hypoglycemia at 26 and 52 weeks (P < 0.001), and total hypoglycemia rates were lower at 52 weeks (P = 0.03). At weeks 26 and 52, glucose variability was lower (P < 0.01), basal insulin dose was higher (P < 0.001), and triglycerides and aminotransferases were higher with BIL versus glargine (P < 0.05). Liver fat content (LFC), assessed in a subset of patients (n = 162), increased from baseline with BIL versus glargine (P < 0.001), with stable levels between 26 and 52 weeks., Conclusions: BIL provided superior glycemic control versus glargine, with reduced nocturnal and total hypoglycemia, lower glucose variability, and increased triglycerides, aminotransferases, and LFC., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Aim: This study evaluated the proportions of prandial (PHG) vs fasting hyperglycaemia (FHG) over 24h in a group of patients with type 2 diabetes (overall and for Caucasian vs Asian patients), and tested the hypothesis that an insulin regimen with a prandial component allows a greater response than basal insulin at low glycated haemoglobin (HbA1c) levels with a higher proportion of PHG than FHG., Methods: Relative contributions of PHG and FHG to overall hyperglycaemia were analyzed by baseline HbA1c quartiles and by ethnicity at baseline and after 24-week treatment with either insulin glargine or insulin lispro mix 25 in the DURABLE study., Results: With increasing baseline HbA1c, the mean relative contribution of PHG to the total area under the curve decreased (from 41% to 27%) while FHG was increased (from 59% to 73%). Both insulins decreased FHG, but only insulin lispro mix 25 decreased PHG. More patients with baseline HbA1c < 9%, where PHG was more relevant, achieved the target HbA1c of < 7% at endpoint with insulin lispro mix 25 compared with glargine. On average, Asians had a 10% larger contribution of PHG at all HbA1c quartiles, and a lower proportion of Asians reached the HbA1c target of < 7% with either insulin treatment compared with Caucasians., Conclusion: At baseline, the contribution of FHG to overall hyperglycaemia predominated at all HbA1c quartiles, whereas PHG was more clinically relevant at lower HbA1c levels and with a greater response to insulin lispro mix 25. Asians had a greater proportion of PHG and a lesser response to either insulins compared with Caucasians. Thus, responses to diabetes drugs by baseline HbA1c and ethnicity are worth investigating to better target and individualize treatment., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Aims: To describe patients with Type 2 diabetes mellitus treated with basal insulin, with or without oral antidiabetics in UK primary care, and evaluate insulin treatment patterns and factors explaining changes in therapy., Methods: Retrospective analysis of patients with Type 2 diabetes within The Health Improvement Network UK primary care database. Patients receiving basal insulin between January and June 2006 were followed until July 2009., Results: Analysis included 3185 patients, mean age 65.6 years [standard deviation (SD) 12.4], 50.9% men, median diabetes duration 9.6 years, median basal insulin use 1.3 years, 86.5% had received oral antidiabetics in the previous 12 months. Mean follow-up was 2.9 years (SD 1.0), 59.8% patients maintained basal insulin throughout follow-up with a mean HbA(1C) of 69 mmol/mol (SD 19; 8.4%, SD 1.7) at baseline and 65 mmol/mol (SD 17; 8.1%, SD 1.6) during follow-up. During follow-up, 6.9% of patients discontinued, 19.3% intensified with and 14.1% switched to prandial or premixed insulin. Patients who intensified (prandial) had a mean HbA(1c) of 77 mmol/mol (SD 18; 9.2%, SD 1.6) before change and a mean HbA(1c) of 71 mmol/mol (SD 21; 8.6%, SD 2.0) at the end of the study. Those switching to premixed insulin had a mean HbA(1c) of 80 mmol/mol (SD 18; 9.5%, SD 1.7) before change and a mean HbA(1c) of 69 mmol/mol (SD 17; 8.5%, SD 1.5) at the end of the study. Increasing HbA(1c) and longer diabetes duration explained intensification and switch., Conclusions: The majority of patients had HbA(1c) above the 53 mmol/mol (< 7%) target at baseline and post-intensification/switch. The HbA(1c) levels were reduced by intensification/switch suggesting that insulin changes did have some impact. Most patients did not change insulin treatment despite having higher than recommended HbA(1c) levels. Reasons for not changing treatment in face of unsatisfactory clinical outcomes are unclear. Further research is warranted to explore barriers towards therapy change., (© 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.)

Background: Prandial premixed therapy 3 times daily has been proposed recently for type 2 diabetes mellitus (T2DM) patients who fail to achieve glycemic control with commonly used premixed insulin analogs, insulin lispro mix 75/25 (LM75/25) and biphasic insulin aspart 70/30 (BIAsp70/30) BID., Objective: The aim of this work was to compare the efficacy and safety of 3-times daily insulin lispro mix 50/50 (TID group) with progressive titration of twice-daily LM75/25 or BIAsp70/30 (BID group) administered along with metformin in T2DM patients., Methods: This was an open-label, 16-week, multicenter, randomized, parallel trial. End point glycosylated hemoglobin (HbA(1c)) was the primary efficacy measure; HbA(1c) reduction from baseline to end point, percentage of patients reaching target HbA(1c) (<7.0% and ≤6.5%), postprandial blood glucose (BG), and BG excursions after lunch were secondary measures. Safety was evaluated by collecting adverse events., Results: A total of 302 patients with mean (SD) age 57.7 (9.27) years, diabetes duration 11.2 (6.47) years, HbA(1c) 8.5% (1.23), fasting BG 184.0 (53.04) mg/dL, body weight 86.8 (14.79) kg, body mass index 31.7 (4.23) kg/m(2), and daily insulin dose ∼48 IU were randomized. No significant difference was observed in end point HbA(1c) between the 2 groups. Seven-point BG profiles showed lower fasting and postbreakfast BG in the BID group but lower postlunch BG in the TID group. Daily insulin dose change was similar in both groups, with more weight gain in the TID group (P = 0.0009). Overall hypoglycemic rates were similar in both groups, but nocturnal hypoglycemia was more frequent in the BID group (P = 0.0063)., Conclusions: In patients with T2DM who have not achieved adequate glycemic control with LM75/25 and BiAsp70/30 BID plus metformin and who are not candidates for basal bolus therapy, switching either to treatment with LM50/50 TID or to progressive titration of premix insulin analogs BID did not produce sufficient evidence of a difference of overall glycemic control between the 2 treatment groups. Short study duration and less intensive dose adjustments might have contributed to these results., (Copyright © 2011 Elsevier HS Journals, Inc. All rights reserved.)

Exenatide, a synthetic peptide originally isolated from salivary secretions of Heloderma suspectum, like other subcutaneously injected peptides, can cause antibody formation. Despite that antibody formation has been observed in some patients, results from previous clinical trials have not shown safety and efficacy concerns in exenatide-naïve patients. The objective of this multicenter, open-label study was to investigate the response of anti-exenatide antibody formation and the incidence of immune-related and hypersensitivity reactions after exenatide re-exposure. Fifty-eight patients (57% male; 59+/-10 years; weight 85+/-19kg; HbA1c 8.1+/-0.9%; duration of diabetes 10+/-5 years) were enrolled. At study initiation, 98.3% of patients were taking 1 or more antidiabetes drugs, including oral medication and various types of insulin. Treatment-emergent adverse events (TEAEs) at any time during the study were observed in 40 and 47% of patients with positive and negative treatment-emergent antibodies, respectively. Immune-related AEs were observed in 6 patients (4 were antibody positive). These AEs had not been reported in their previous exposure to exenatide. Re-exposure to exenatide did not result in increased hypersensitivity reactions. Overall, 72% of patients had a baseline to endpoint reduction in HbA1c (range -0.1 to -2.8%), and 87% of antibody negative versus 62% of antibody positive patients had an HbA1c endpoint reduction. The study design and the patients' baseline characteristics, including diabetes treatment at study initiation, are confounding factors limiting clinical conclusions on exenatide's glycemic effect in this patient population. The study results indicate that anti-exenatide antibody formation did not increase the incidence of TEAEs in patients re-exposed to exenatide.

In an open-label, 24-week, parallel-group study, 135 patients inadequately controlled with oral antihyperglycemic medications (OAMs) were treated with maximally tolerated doses of metformin and glibenclamide for at least 8 weeks and then randomized to bedtime neutral protamine Hagedorn (NPH) insulin plus maximally tolerated dose of glibenclamide BID (glib/NPH group) or insulin lispro mix 50 (50% lispro, 50% insulin lispro protamine suspension [ILPS]) pre-breakfast and lispro mix 25 (25% lispro, 75% ILPS) pre-dinner (LM50/LM25 group) (both OAMs discontinued). The LM50/LM25 group had significantly lower 2-hour postprandial BG (both meals combined) compared with glib/NPH after 12 (11.70+/-3.40 mmol/L vs. 13.15+/-2.44 mmol/L, p=0.010) and 24 weeks (11.13+/-3.31 mmol/L vs. 14.46+/-2.93 mmol/L, p =0.0001). Both regimens significantly decreased HbA1c. The reduction was greater with LM50/LM25 (-1.31+/-2% vs. -0.5+/-1.6%; P=0.01). At endpoint, the overall hypoglycemia rate increased with LM50/LM25 and decreased with glib/NPH compared with baseline (0.22+/-0.9 vs. -0.08+/-0.72 episodes/patient/30 days; p =0.037). Treatment with LM50/LM25 compared with glib/NPH in patients with inadequate control on combined OAMs yielded better postprandial and overall glycemic control with a higher rate of hypoglycemia.