To compare the efficacy and safety of a twice daily injection of insulin aspart (BIAsp) 30 and BIAsp50 in patients with type 2 diabetes mellitus (T2DM) poorly controlled with oral hypoglycemic agents (OHAs).

In this 12 week prospective, randomized, parallel trial, a total of 80 T2DM patients, 59 ± 10 years old with a disease duration of 9.3 ± 6.6 years and HbA1c >7% despite large doses of metformin and sulfonylurea administration, were randomized to receive BIAsp30 (n = 40) or BIAsp50 (n = 40). The primary endpoint was a change in HbA1c at week 12.

The changes in HbA1c from baseline were -2.5% ± 1.0% in the BIAsp50 group and -2.5% ± 1.2% in the BIAsp30 group (p = .897). No difference was observed in the rate of HbA1c target achievement (<7.0%) between BIAsp50 (42.5%) and BIAsp30 (32.5%) (p = .495). The change in fasting plasma glucose (FPG) in the BIAsp50 group was lower than that in the BIAsp30 group (p < .001), while the change in two-hour postprandial blood glucose (2hPBG) was higher and blood glucose excursion was lower in the BIAsp50 group than that in the BIAsp30 group (p < .001, p < .001). A significant improvement in HbA1c was observed with BIAsp50 in subgroups with baseline blood glucose excursion >7.8 mmol/L or 2hPBG >17.6 mmol/L compared with BIAsp30. There were no differences in hypoglycemia or body weight between groups.

Compared with BIAsp30, BIAsp50 showed greater efficacy in patients with baseline BG excursion >7.8 mmol/L or 2hPBG >17.6 mmol/L as well as good safety for hypoglycemia.

ChiCTR-IIR-16008958.

We compared the effects of insulin lispro mix 25 (LM25) and insulin lispro mix 50 (LM50) on postprandial glucose excursion in patients with type 2 diabetes mellitus (T2DM).

In this randomized, open-label, investigator-initiated trial, 81 T2DM patients treated with premixed human insulin 70/30 (PHI70/30) for more than 90 days were randomly divided into two groups and received a crossover protocol of either LM25 or LM50 twice daily for 16 weeks. Continuous glucose monitoring (CGM) was performed for 72 h at baseline and at the end of each treatment phase to evaluate glycemic excursions in the subjects.

The LM50 regimen resulted in significantly smaller postprandial glycemic excursions than the LM25 regimen after breakfast (1.3 ± 2.5 vs. 2.4 ± 2.6 mmol/L, P = 0.046) and dinner (1.5 ± 2.8 vs. 2.8 ± 2.4 mmol/L, P = 0.036). Glycosylated hemoglobin levels were similar for the patients on the three regimens. The percentage of patients who achieved their glycosylated hemoglobin target was significantly higher for the LM25 and LM50 regimens than for the PHI70/30 regimen, regardless of whether the target was set at 7.0% or 6.5%. The proportion of the patients who were hypoglycemic for a high percentage (> 10%) of the time was lower for the LM50 regimen than for the LM25 and PHI70/30 regimens.

LM50 may provide better glycemic excursion control after breakfast and dinner than LM25 in T2DM patients.

http://www.chictr.org.cn # ChiCTR-TTRCC-12002516.

Lilly Suzhou Pharmaceutical Co., Ltd. (Shanghai Branch, China) and National Key Program of Clinical Science of China (WBYZ 2011-873).

Premixed insulin analogs represent an alternative to basal or basal-bolus insulin regimens for the treatment of type 2 diabetes (T2D). "Low-mix" formulations with a low rapid-acting to long-acting analog ratio (e.g., 25/75) are commonly used, but 50/50 formulations (Mix50) may be more appropriate for some patients. We conducted a systematic literature review to assess the efficacy and safety of Mix50, compared with low-mix, basal, or basal-bolus therapy, for insulin initiation and intensification.

MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, ClinicalTrials.gov, LillyTrials.com, and NovoNordisk-trials.com were searched (11 or 13 Dec 2016) using terms for T2D, premixed insulin analogs, and/or Mix50. Studies (randomized, nonrandomized, or observational; English only) comparing Mix50 with other insulins (except human) and reporting key efficacy [glycated hemoglobin (HbA1c), fasting and postprandial glucose] and/or safety (hypoglycemia, weight gain) outcomes were eligible for inclusion. Narrative reviews, letters, editorials, and conference abstracts were excluded. Risk of bias in randomized trials was assessed using the Cochrane tool.

MEDLINE and EMBASE searches identified 716 unique studies, of which 32 met inclusion criteria. An additional three studies were identified in the other databases. All 19 randomized trials except one were open label; risk of other biases was generally low. Although not conclusive, the evidence suggests that Mix50 may provide better glycemic control (HbA1c reduction) and, particularly, postprandial glucose reduction in certain patients, such as those with high carbohydrate diets and Asian patients, than low-mix and basal therapy. Based on this evidence and our experience, we provide clinical guidance on factors to consider when deciding whether Mix50 is appropriate for individual patients.

Mix50 may be more suitable than low-mix therapy for certain patients. Clinicians should consider not only efficacy and safety but also patient characteristics and preferences when tailoring insulin treatment to individuals with T2D.

Eli Lilly.

In Japan, premixed insulins are commonly used as starter insulin for type 2 diabetes. This subpopulation analysis assessed the efficacy and safety of twice-daily LM25 (25% insulin lispro/75% insulin lispro protamine) and LM50 (50% insulin lispro/50% insulin lispro protamine) as starter insulin in Japanese subjects, and compared these results with the whole-trial populations of East Asian subjects. In this subpopulation analysis of an open-label, phase 4, randomized trial (CLASSIFY), Japanese subjects received LM25 (n = 88) or LM50 (n = 84) twice-daily for 26 weeks. The primary outcome was change from baseline at Week 26 in glycated hemoglobin (HbA1c). Results for Japanese subjects were generally similar to those for the whole-trial population. Similar changes from baseline in HbA1c were observed for LM25 and LM50 groups (least squares [LS] mean difference [95% confidence interval] of LM25 - LM50 = 0.13 [-0.16, 0.41]%, 1.42 [-1.75, 4.48] mmol/mol, p = 0.388). More LM50-treated subjects than LM25-treated subjects achieved HbA1c targets of <7.0% (59.5% versus 43.2%; p = 0.034) or ≤6.5% (45.2% versus 28.4%; p = 0.027). The reduction in postprandial blood glucose concentrations after morning and evening meals was statistically significantly greater for LM50 than for LM25. The incidence of both hypoglycemia and treatment-emergent adverse events were similar between treatment groups. Both LM25 and LM50 twice daily appear to be effective and well tolerated as starter insulin, although LM50 might be more effective for Japanese type 2 diabetes patients.

Premixed insulins are recommended starter insulins in Chinese patients after oral antihyperglycemic medication (OAM) failure. In the present study, we compared the efficacy and safety of insulin lispro mix 25 (LM25) twice daily (b.i.d.) and insulin lispro mix 50 (LM50) b.i.d. as a starter insulin regimen in Chinese patients with type 2 diabetes mellitus (T2DM) who had inadequate glycemic control with OAMs.

The primary efficacy outcome in the present open-label parallel randomized clinical trial was change in HbA1c from baseline to 26 weeks. Patients were randomized in a ratio of 1:  1 to LM25 (n = 80) or LM50 (n = 76). A mixed-effects model with repeated measures was used to analyze continuous variables. The Cochran-Mantel-Haenszel test with stratification factor was used to analyze categorical variables.

At the end of the study, LM50 was more efficacious than LM25 in reducing mean HbA1c levels (least-squares [LS] mean difference 0.48; 95 % confidence interval [CI] 0.22, 0.74; P < 0.001). More subjects in the LM50 than LM25 group achieved HbA1c targets of <7.0 % (72.4 % vs 45.0 %; P = 0.001) or ≤6.5 % (52.6 % vs 20.0 %; P < 0.001). Furthermore, LM50 was more effective than LM25 at reducing HbA1c in patients with baseline HbA1c, blood glucose excursion, and postprandial glucose greater than or equal to median levels (P ≤ 0.001). The rate and incidence of hypoglycemic episodes and increase in weight at the end of the study were similar between treatment groups.

In Chinese patients with T2DM, LM50 was more efficacious than LM25 as a starter insulin.

Lispro Mix 25% insulin lispro/75% insulin lispro protamine (LM25) and Lispro Mix 50% insulin lispro/50% insulin lispro protamine (LM50) were compared as starter insulins in East Asian patients with type 2 diabetes.

Phase 4, open-label, randomized trial conducted in China, Japan, Korea, and Turkey. Subjects received twice-daily LM25 (n = 207) or LM50 (n = 196) for 26 weeks. The primary outcome was the HbA_1c change from baseline.

The least squares mean changes from baseline in HbA_1c are -1.52% and -1.69% for LM25 and LM50, respectively, and the least squares mean difference [95% CI] is 0.17% [-0.01, 0.35]. More subjects in the LM50 group than in the LM25 group achieved HbA_1c targets of <7.0% (59.7% versus 45.9%, respectively; p = 0.007). LM50 was more effective than LM25 in reducing postprandial glucose after the morning (mean difference in change from baseline, 0.56 mmol/L; p = 0.038) and evening (1.11 mmol/L; p < 0.001) meals. The reduction in fasting blood glucose was significantly greater (p = 0.046) in the LM25 group (LS mean [95% CI] change from baseline: -2.37 mmol/L [-2.68, -2.06]) than in the LM50 group (-1.99 mmol/L [-2.30, -1.68]). LM50 was more effective than LM25 in reducing HbA_1c in subjects with baseline HbA_1c , postprandial glucose, or carbohydrate intake levels greater than the median levels. Hypoglycemia rates and weight gain were similar between groups.

LM25 and LM50 were noninferior to each other in improving glycemic control in Asian patients with type 2 diabetes. In addition, LM50 was more efficacious than LM25 with respect to the percentage of subjects reaching target HbA_1c levels. Copyright © 2016 John Wiley & Sons, Ltd.

Diabetes is a growing public health concern. Effective use of therapies for this chronic disease is necessary to improve long-term prognosis, but treatment adherence can be difficult to promote in clinical practice, and insulin, in particular, can impact both positively and negatively on patients' quality of life (QoL). Currently, guidelines advocate for QoL as a treatment goal in its own right, with treatment decisions based on patient concerns regarding injection frequency and adverse events, as well as glycemic control. Successful insulin management ideally requires a regimen to replicate normal endogenous insulin release, and this was a key driver in the development of insulin analogs. These analogs have also been associated with lower hypoglycemia risk, lower levels of postprandial glucose excursions, better adherence, improved QoL, and higher patient satisfaction with treatment. Premixed insulin is prescribed for many patients with type 2 diabetes mellitus (T2D), as it combines both prandial and basal treatment, reducing the number of injections. Evidence suggests that premixed insulin analogs have advantages over conventional premixed human insulin for T2D treatment, but the objective of this review was to assess the evidence that switching from a biphasic human insulin to a biphasic insulin analog regimen improves patient QoL.

Novo Nordisk.

This study aims to investigate the metabolic effects of biphasic insulin lispro 50/50 in routine clinical practice. A total of 229 patients who were ≥18 years old with diabetes, newly treated with biphasic insulin lispro 50/50, were sourced from six secondary care services in England.

Detailed clinical parameters were compared at baseline, and 3 and 6 months post-initiation. Responders was defined as those with HbA1c <7.5% (58 mmol/mol) and/or an HbA1c reduction of >1% (11 mmol/mol) at 6 months.

HbA1c showed significant reduction: -0.93% (-10 mmol/mol) and -1.2% (-13 mmol/mol) at 3 and 6 months respectively, while no significant change was noted for all the other parameters. When analyzed according to frequencies of injections/day, the greatest reduction was observed with the three times a day regimen (-1.0% [-11.0 mmol/mol] and -1.3% [-14.6 mmol/mol] at 3 and 6 months respectively). HbA1c reduction was greatest in the group who previously received a basal-bolus insulin regimen: (-0.8% [-9.0 mmol/mol] and -1.5% [-16.2 mmol/mol] at 3 and 6 months respectively). Reduction in weight was observed at 3 months (-1.8 kg ± 4.3) only for those who were previously on a basal-bolus insulin regimen. Insulin doses increased following conversion to biphasic insulin lispro 50/50, irrespective of the types of insulin used prior to biphasic insulin lispro 50/50, but this was not associated with weight gain. The independent predictors of response to biphasic insulin lispro 50/50 were baseline HbA1c, Caucasian, presence of nephropathy, prior use of basal-bolus insulin and prior use of other premixed combination.

Biphasic insulin lispro 50/50 is therefore an effective therapeutic option for achieving glycemic control in patients with suboptimal HbA1c levels, especially among those who were previously on a basal-bolus insulin regimen and those who received it three times daily, with a neutral effect on weight parameters.

This was a retrospective study of routine clinical practice and is therefore limited by allocation bias and some missing data. Information on rates of hypoglycemia and quality of life are not available.

This article reviews the epidemiological evidence linking diabetes and gastric cancer and discusses some of the potential mechanisms, confounders and biases in the evaluation of such an association. Findings from four meta-analyses published from 2011 to 2013 suggest a positive link, which may be more remarkable in females and in the Asian populations. Putative mechanisms may involve shared risk factors, hyperglycemia, Helicobacter pylori (H. pylori) infection, high salt intake, medications and comorbidities. Diabetes may increase the risk of gastric cancer through shared risk factors including obesity, insulin resistance, hyperinsulinemia and smoking. Hyperglycemia, even before the clinical diagnosis of diabetes, may predict gastric cancer in some epidemiological studies, which is supported by in vitro, and in vivo studies. Patients with diabetes may also have a higher risk of gastric cancer through the higher infection rate, lower eradication rate and higher reinfection rate of H. pylori. High salt intake can act synergistically with H. pylori infection in the induction of gastric cancer. Whether a higher risk of gastric cancer in patients with diabetes may be ascribed to a higher intake of salt due to the loss of taste sensation awaits further investigation. The use of medications such as insulin, metformin, sulfonylureas, aspirin, statins and antibiotics may also influence the risk of gastric cancer, but most of them have not been extensively studied. Comorbidities may affect the development of gastric cancer through the use of medications and changes in lifestyle, dietary intake, and the metabolism of drugs. Finally, a potential detection bias related to gastrointestinal symptoms more commonly seen in patients with diabetes and with multiple comorbidities should be pointed out. Taking into account the inconsistent findings and the potential confounders and detection bias in previous epidemiological studies, it is expected that there are still more to be explored for the clarification of the association between diabetes and gastric cancer.

This study aims to examine the metabolic effects of intensification or initiation of insulin treatment with biphasic insulin 50/50, and determine the predictors of responders or non-responders to biphasic insulin 50/50.

A cohort of 2183 patients ≥18 years with diabetes, newly treated with biphasic insulin 50/50 between January 2000 and May 2012, were sourced from UK General Practices via The Health Improvement Network (THIN) database. Baseline clinical parameters of 1267 patients with suboptimal glycated hemoglobin (HbA1c) >7.5% (>58 mmol/mol) who had received background insulin regimens for at least 6 months preceding biphasic insulin 50/50 were compared against 12-month outcome data. Responders were defined as those with HbA1c <7.5% (58 mmol/mol) and/or HbA1c reduction of ≥1% (10.9 mmol/mol) at 12 months. Comparative analyses were carried out on subgroups of 237 patients initiating insulin therapy with biphasic insulin 50/50, and between users of the Humalog Mix50 (HM50) versus Insuman Comb 50 (IC50). Associations were examined using t tests and multivariate logistic regression techniques.

The overall mean HbA1c reduction at 12 months as a result of intensification and initiation with biphasic insulin 50/50 was 0.5% (5.5 mmol/mol) and 1.6% (17.5 mmol/mol), respectively. Adjusted ORs show obesity (body mass index >30 kg/m(2)), treatment duration for ≥9 months, and baseline HbA1c are independent determinants of responders. In addition, stratified for baseline HbA1c levels, HM50 was associated with better HbA1c outcome compared with IC50.

biphasic insulin 50/50 is effective for achieving glycemic control in suboptimal HbA1c levels, especially among obese patients with insulin-treated diabetes. Stratified for baseline HbA1c, HM50 was associated with improved HbA1c outcome compared with IC50.