Systemic Anti-Inflammatory Therapy Aided by Curcumin-Laden Double-Headed Nanoparticles Combined with Injectable Long-Acting Insulin in a Rodent Model of Diabetes Eye Disease.

Therapeutic interventions that counter emerging targets in diabetes eye diseases are lacking. We hypothesize that a combination therapy targeting inflammation and hyperglycemia can prevent diabetic eye diseases. Here, we report a multipronged approach to prevent diabetic cataracts and retinopathy by combining orally bioavailable curcumin-laden double-headed (two molecules of gambogic acid conjugated to terminal carboxyl groups of poly(d,l-lactide-co-glycolide)) nanoparticles and injectable basal insulin. The combination treatment led to a significant delay in the progression of diabetic cataracts and retinopathy, improving liver function and peripheral glucose homeostasis. We found a concurrent reduction in lens aggregate protein, AGEs, and increased mitochondrial ATP production. Importantly, inhibition of Piezo1 protected against hyperglycemia-induced retinal vascular damage suggesting possible involvement of Piezo1 in the regulation of retinal phototransduction. Histologic evaluation of murine small intestines revealed that chronic administration of curcumin-laden double-headed nanoparticles was well tolerated, circumventing the fear of nanoparticle toxicity. These findings establish the potential of anti-inflammatory and anti-hyperglycemic combination therapy for the prevention of diabetic cataracts and retinopathy.

Impact of Insulin Degludec in Hospitalized Patients With and Without Type 2 Diabetes Requiring Parenteral/Enteral Nutrition: An Observational Study.

INTRODUCTION: Hyperglycemia in inpatients is a major problem, especially when nutritional support is required. This study aims to assess the impact of treatment with insulin degludec (IDeg) on mean blood glucose (BG) and glycemic variability in noncritical hospitalized patients with and without type 2 diabetes (T2DM) receiving enteral and/or parenteral nutrition (EN, PN). METHODS: Mean BG and glycemic variability from admission up to 7 days of hospitalization were evaluated in consecutive cases with and without T2DM. Percentage of coefficient of variation (CV) for glucose was used to express glycemic variability. RESULTS: Overall, 26 patients (13 with and 13 without T2DM) were admitted to the hospital for any cause. Subjects were 65.4% men and they were mainly elderly (mean age 66.3 ± 13.4 years). PN was administered in 88.5% of patients and EN in 19.2%. At admission, mean HbA1c level was 5.9 ± 0.7% in patients without diabetes and 9.1 ± 2.5% in patients with T2DM. During hospitalization, mean daily BG levels changed from 151 ± 47.3 mg/dl (day 1) to 157 ± 66.7 mg/dl (day 7) in patients without diabetes and from 210 ± 66.5 mg/dl to 192 ± 48.6 mg/dl in patients with T2DM. CV decreased from 14% (day 1) to 11% (day 7) in patients without diabetes and from 20% (day 1) to 9% (day 7) in patients with T2DM. No symptomatic or severe hypoglycemia occurred. CONCLUSIONS: Despite the small sample size and the lack of control group, this study represents the first proof-of-concept that IDeg in hospitalized patients with or without T2DM who require nutritional support has the potential to maintain stable levels of BG and reduce glycemic variability. FUNDING: Novo Nordisk S.p.A. grant.

Transition from intravenous insulin to subcutaneous long-acting insulin in critical care patients on enteral or parenteral nutrition / Transición de insulina intravenosa a insulina de acción prolongada subcutánea en pacientes de cuidados críticos con nutrición enteral o parenteral

Background and aims: The optimal initial dose of subcutaneous (SC) insulin after intravenous (IV) infusion is controversial, especially in patients receiving continuous enteral nutrition (EN) or total parenteral nutrition (TPN). The aim of this study was to evaluate the strategy used at our hospital intensive care unit (ICU) in patients switched from IV insulin to SC insulin glargine while receiving EN or TPN. Design and methods: A retrospective analysis was made of 27 patients on EN and 14 on TPN switched from IV infusion insulin to SC insulin. The initial dose of SC insulin was estimated as 50% of the daily IV insulin requirements, extrapolated from the previous 12h. A corrective dose of short-acting insulin (lispro) was used when necessary. Results: Mean blood glucose (BG) level during SC insulin treatment was 136±35mg/dL in the EN group and 157±37mg/dL in the TPN group (p=0.01). In the TPN group, mean BG was >180mg/dL during the first three days after switching, and a 41% increase in the glargine dose was required to achieve the target BG. In the EN group, mean BG remained <180mg/dL throughout the days of transition and the dose of glargine remained unchanged. Conclusions: In the transition from IV to SC insulin therapy, initial insulin glargine dose estimated as 50% of daily IV insulin requirements is adequate for patients on EN, but inadequate in those given TPN (AU)

Introducción y objetivo: La dosis óptima inicial de insulina subcutánea (SC) después de la infusión intravenosa (IV) es controvertida, especialmente en pacientes que reciben nutrición enteral continua (NE) o nutrición parenteral total (NPT). El objetivo de este estudio fue evaluar la estrategia utilizada en nuestra unidad de cuidados intensivos (UCI) en pacientes sometidos a transición de infusión IV a insulina glargina SC mientras recibían NE o NPT. Diseño y métodos: Se analizaron retrospectivamente 27 pacientes con NE y 14 con NPT que cambiaron de infusión IV a insulina SC. La dosis inicial de insulina SC se estimó como el 50% de los requerimientos diarios de insulina IV, extrapolado de las 12 horas anteriores. Se utilizó dosis correctiva de insulina ultrarrápida (lispro), cuando fue necesaria. Resultados: La media de glucemia plasmática (GP) con insulina SC fue de 136,35mg/dl en el grupo NE y de 157,37mg/dl en el grupo NPT, p=0.01. En el grupo de NPT la GP media fue>180mg/dL durante los tres primeros días después de la transición y fue necesario un aumento del 41% en la dosis de glargina para alcanzar la GP objetivo. En el grupo NE, la GP media permaneció<180mg/dl durante los días de transición y la dosis de glargina permaneció sin cambios. Conclusiones: En la transición de la terapia de insulina IV a insulina SC, la dosis inicial de insulina glargina estimada como el 50% de los requerimientos diarios de insulina IV es adecuada para los pacientes que reciben NE, pero insuficiente para los que reciben NPT (AU)

Cost-effectiveness of insulin degludec compared with insulin glargine in a basal-bolus regimen in patients with type 1 diabetes mellitus in the UK.

OBJECTIVE: The aim of this study was to evaluate the cost-effectiveness of insulin degludec (IDeg) vs insulin glargine (IGlar) as part of a basal-bolus treatment regimen in adults with T1DM, using a short-term economic model. METHODS: Data from two phase III clinical studies were used to populate a simple and transparent short-term model. The costs and effects of treatment with IDeg vs IGlar were calculated over a 12-month period. The analysis was conducted from the perspective of the UK National Health Service. Sensitivity analyses were conducted to assess the degree of uncertainty surrounding the results. The main outcome measure, the incremental cost-effectiveness ratio (ICER), was the cost per quality-adjusted life-year (QALY). RESULTS: IDeg is a cost-effective treatment option vs IGlar in patients with T1DM on a basal-bolus regimen. The base case ICER was estimated at £16,895/QALY, which is below commonly accepted thresholds for cost-effectiveness in the UK. Sensitivity analyses demonstrated that the ICER was stable to variations in the majority of input parameters. The parameters that exerted the most influence on the ICER were hypoglycemia event rates, daily insulin dose, and disutility associated with non-severe nocturnal hypoglycemic events. However, even under extreme assumptions in the majority of analyses the ICERs remained below the commonly accepted threshold of £20,000-£30,000 per QALY gained. CONCLUSIONS: This short-term modeling approach accommodates the treat-to-target trial design required by regulatory bodies, and focuses on the impact of important aspects of insulin therapy such as hypoglycemia and dosing. For patients with T1DM who are treated with a basal-bolus insulin regimen, IDeg is a cost-effective treatment option compared with IGlar. IDeg may be particularly cost-effective for sub-groups of patients, such as those suffering from recurrent nocturnal hypoglycemia and those with impaired awareness of hypoglycemia.

Effects of basal insulin glargine and omega-3 fatty acid on cognitive decline and probable cognitive impairment in people with dysglycaemia: a substudy of the ORIGIN trial.

BACKGROUND: Diabetes and non-diabetic dysglycaemia are risk factors for accelerated cognitive decline. In this planned substudy of the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial, we assessed whether normalising glucose with insulin glargine or administering omega-3 fatty acids in this population may slow this process or affect the development of cognitive impairment. METHODS: The ORIGIN trial recruited participants older than 50 years with dysglycaemia who were taking either no or one oral glucose-lowering drug, who had additional risk factors for cardiovascular events, whose HbA1c was less than 9%, and who were not taking insulin. Participants were recruited from 573 sites in 40 countries. Participants were randomly assigned to either titrated basal insulin glargine targeting a fasting plasma glucose concentration of 5.3 mmol/L or lower or standard care and to either omega-3 fatty acid (1 g) or placebo by a factorial design. Outcome adjudicators and data analysts were masked to treatment allocation. Cognitive function was assessed by the Mini-Mental State Examination (MMS) and Digit Symbol Substitution (DSS). The effect of insulin glargine or omega-3 fatty * acid on cognitive function over time, the annualised change in test scores, and the development of probable cognitive impairment were measured. All analyses were restricted to those participants who had a cognitive measurement at both baseline and at least one follow-up visit. The ORIGIN trial is registered with ClinicalTrials.gov, NCT00069784. FINDINGS: Participants were randomly assigned between Sept 1, 2003, and Dec 15, 2005. MMSE and DSS were assessed in 11,685 and 3392 ORIGIN participants (mean age 63.4 years [SD 7.7]), who were followed up for a median of 6.2 years (IQR 5.8-6.7). There was no difference in the rate of change of cognitive test scores between the insulin glargine and standard care groups (for the MMSE 0.0046, 95% CI -0.0132 to 0.0224, p=0.39; and for the DSS -0.0362, -0.2180 to 0.1455, p=0.34) or between the omega-3 fatty acid and placebo groups (for the MMSE 0.0013, 95% CI -0.0165 to 0.0191, p=0.21; and for the DSS -0.0605, -0.2422 to 0.1212, p=0.72). Similarly, the incidence of probable cognitive impairment did not differ between the insulin glargine and standard care groups (p=0.065) or the omega-3 fatty acid and placebo groups (p=0.070). In a subgroup analysis, allocation to insulin glargine versus standard care seemed to reduce the decline in the MMSE (but not the DSS) in participants with dysglycaemia but without evidence of diabetes (pinteraction=0.024). INTERPRETATION: In this relatively young cohort of people with dysglycaemia, insulin mediated normoglycaemia and omega-3 fatty acid for over 6 years had a neutral effect on the rate of cognitive decline and on incident cognitive impairment. Future studies should assess the effect of these interventions in an older cohort or the effect of other glucometabolic interventions on cognitive decline. FUNDING: Sanofi.

More satisfied, but why? A pooled patient-level analysis of treatment satisfaction following the initiation of insulin glargine vs. comparators in insulin-naïve patients with type 2 diabetes mellitus.

AIM: To assess patient-reported outcomes associated with initiating insulin glargine among insulin-naïve patients with type 2 diabetes mellitus (T2DM). METHODS: This was a pooled analysis of patient-level data from Phase 3, randomized controlled trials evaluating once-daily insulin glargine vs. comparator treatment for ≥24 weeks in previously insulin-naïve adult patients with T2DM and poor glycaemic control. Eligible studies utilized strict, predefined insulin titration algorithms with weekly dose-adjustment to achieve fasting plasma glucose (FPG) levels of ≤5.6 mmol/l. Treatment satisfaction was measured using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) change (c) and status (s) versions. RESULTS: A total of 1577 patients from four studies were included; 830 patients treated with insulin glargine and 747 with comparators. At week 24, DTSQc scores improved in both groups with a significantly higher increase in treatment satisfaction for insulin glargine vs. comparators (13.5 vs. 12.1; p < 0.0001). Multivariate regression analysis revealed that significant predictors of DTSQc improvement at week 24 were insulin glargine treatment (p < 0.0001), higher baseline DTSQs (p < 0.0001), and lower baseline body weight (p = 0.0103). Greater improvement in DTSQc at week 24 was significantly associated with decrease from baseline in glycosylated haemoglobin (p < 0.001) and FPG (p = 0.0001); a numerically more positive change in weight from baseline approached significance (p = 0.07). CONCLUSION: Initiation of insulin glargine in insulin-naïve patients with T2DM is associated with greater improvements in treatment satisfaction than alternative interventions, with perceived improvements in glycaemic control and baseline weight likely to be important factors.

[What has the largest study in the history of diabetology brought us?]. / Co nám prinesla nejvetsí studie v historii diabetologie?

UNLABELLED: The main objective of the ORIGIN study was an observation of the effects of treatment with insulin analogue, insulin glargine on cardiovascular complications in patients with severe atherosclerosis and early stages of well-compensated diabetes and prediabetes. The authors expected that a long-term reduction of glycaemia on an empty stomach will reduce the number of occurrences of cardiovascular complications. The study, which was conducted over a period of more than six years, showed neither a positive nor a negative effect of insulin treatment on cardiovascular complications. The second main objective of the study was the following: to compare the effect of the omega-3 fatty acid treatment versus placebo on the development of cardiovascular complications. However, no influence of n-3 fatty acids on the development of cardiovascular complications was found. The study investigated whether the insulin glargine treatment leads to an increased number of cancer occurrences. No correlation between cancer and the insulin glargine treatment was proven in this study. Long-term insulin treatment in the early stages of diabetes led to a minimal increase in weight through the course of six years (1.5 kg) and to three times more hypoglycaemia occurrences compared to placebo. However, the number of hypoglycaemia occurrences was very small. CONCLUSION: The study has confirmed the safety of the insulin glargine treatment combined with metformin in the early stages of diabetes, without an increased number of atherosclerosis or cancer occurrences, and with minimal weight gain.

Effect of insulin glargine and n-3FA on carotid intima-media thickness in people with dysglycemia at high risk for cardiovascular events: the glucose reduction and atherosclerosis continuing evaluation study (ORIGIN-GRACE).

OBJECTIVE: To evaluate the effects of insulin glargine and n-3 polyunsaturated fatty acid (n-3FA) supplements on carotid intima-media thickness (CIMT). RESEARCH DESIGN AND METHODS: We enrolled 1,184 people with cardiovascular (CV) disease and/or CV risk factors plus impaired fasting glucose, impaired glucose tolerance, or early type 2 diabetes in a randomized multicenter 2 × 2 factorial design trial. Participants received open-label insulin glargine (targeting fasting glucose levels ≤ 5.3 mmol/L [95 mg/dL]) or standard glycemic care and double-blind therapy with a 1-g capsule of n-3FA or placebo. The primary trial outcome was the annualized rate of change in maximum CIMT for the common carotid, bifurcation, and internal carotid artery segments. Secondary outcomes were the annualized rates of change in maximum CIMT for the common carotid and the common carotid plus bifurcation, respectively. Baseline followed by annual ultrasounds were obtained during a median follow-up of 4.9 years. RESULTS: Compared with standard care, insulin glargine reduced the primary CIMT outcome, but the difference was not statistically significant (difference = 0.0030 ± 0.0021 mm/year; P = 0.145) and significantly reduced the secondary CIMT outcomes (differences of 0.0033 ± 0.0017 mm/year [P = 0.049] and 0.0045 ± 0.0021 mm/year [P = 0.032], respectively). There were no differences in the primary and secondary outcomes between the n-3FA supplement and placebo groups. CONCLUSIONS: In people with CV disease and/or CV risk factors and dysglycemia, insulin glargine used to target normoglycemia modestly reduced CIMT progression, whereas daily supplementation with n-3FA had no effect on CIMT progression.

n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia.

BACKGROUND: The use of n-3 fatty acids may prevent cardiovascular events in patients with recent myocardial infarction or heart failure. Their effects in patients with (or at risk for) type 2 diabetes mellitus are unknown. METHODS: In this double-blind study with a 2-by-2 factorial design, we randomly assigned 12,536 patients who were at high risk for cardiovascular events and had impaired fasting glucose, impaired glucose tolerance, or diabetes to receive a 1-g capsule containing at least 900 mg (90% or more) of ethyl esters of n-3 fatty acids or placebo daily and to receive either insulin glargine or standard care. The primary outcome was death from cardiovascular causes. The results of the comparison between n-3 fatty acids and placebo are reported here. RESULTS: During a median follow up of 6.2 years, the incidence of the primary outcome was not significantly decreased among patients receiving n-3 fatty acids, as compared with those receiving placebo (574 patients [9.1%] vs. 581 patients [9.3%]; hazard ratio, 0.98; 95% confidence interval [CI], 0.87 to 1.10; P=0.72). The use of n-3 fatty acids also had no significant effect on the rates of major vascular events (1034 patients [16.5%] vs. 1017 patients [16.3%]; hazard ratio, 1.01; 95% CI, 0.93 to 1.10; P=0.81), death from any cause (951 [15.1%] vs. 964 [15.4%]; hazard ratio, 0.98; 95% CI, 0.89 to 1.07; P=0.63), or death from arrhythmia (288 [4.6%] vs. 259 [4.1%]; hazard ratio, 1.10; 95% CI, 0.93 to 1.30; P=0.26). Triglyceride levels were reduced by 14.5 mg per deciliter (0.16 mmol per liter) more among patients receiving n-3 fatty acids than among those receiving placebo (P<0.001), without a significant effect on other lipids. Adverse effects were similar in the two groups. CONCLUSIONS: Daily supplementation with 1 g of n-3 fatty acids did not reduce the rate of cardiovascular events in patients at high risk for cardiovascular events. (Funded by Sanofi; ORIGIN ClinicalTrials.gov number, NCT00069784.).