insulin-glargine and Diabetic-Retinopathy

Insulin analogues were developed to modify the structure of the human insulin molecule in order to more accurately approximate the endogenous secretion of insulin. With the help of recombinant technology and site-directed mutagenesis, the insulin molecule can be modified to either delay or shorten absorption time, providing better insulin treatment options and facilitating the achievement of glycaemic goals. Changing the structure of the insulin molecule, however, may significantly alter both its metabolic and mitogenic activity. Multiple factors such as residence time on the receptor, dissociation rate, rate of receptor internalization and the degree of phosphorylation of signalling proteins can affect the mitogenic potencies of insulin analogues. Changes in the structure of the insulin have raised concern about the safety of the insulin analogues. For example, questions have emerged about the relationship between the use of insulin lispro and insulin glargine and the progression of diabetic retinopathy. Two studies have shown progression of retinopathy with the use of insulin lispro. However, others have not confirmed these results, and causality could not be proven as progression of retinopathy can occur with rapid improvement in glycaemic control, and methods of assessments among studies were not consistent. Therefore, we examine the metabolic and mitogenic characteristics of the three insulin analogues, insulin lispro, insulin aspart and insulin glargine, that are currently on the market, as well as the two insulin analogues, insulin glulisine and insulin detemir, that are soon going to be available for clinical use.

Topics: Diabetic Retinopathy; Disease Progression; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Aspart; Insulin Glargine; Insulin Lispro; Insulin, Long-Acting; Mitogens; Pregnancy; Pregnancy in Diabetics; Prenatal Exposure Delayed Effects

In this study, we compared the effect on diabetic retinopathy (DR) between oral antidiabetic drugs (OADs) alone and in combination with basal insulin-supported OADs therapy (BOT). [Correction added on 11 November 2019, after first online publication: In Abstract under Background section, "DR" has been corrected into "diabetic retinopathy (DR)".] METHODS: Between January 2015 and January 2018, this study enrolled 290 patients (age 18-65 years) with diabetes duration between 0 and 5 years. Patients were randomly assigned to receive OADs or BOT after 14 days intensive insulin treatment. Examinations were performed at the beginning and end of the study.. Fewer patients developed DR in the BOT than OADs group (8 [6.06%] vs 12 [8.3%], respectively), and all cases of DR were non-proliferative. Blood glucose concentrations were higher in the BOT than OADs group at the 3rd month, but lower in the former at the 6th and 12th month. The rate of reaching target HbA1c ≤7% was lower in the BOT than OADs group at the 3rd month (63.6% vs 72.2%, respectively), similar between the two groups at the 6th month (60.6% vs 66.6%, respectively) and higher in the BOT group at the 12th month (75.0% vs 61.1%, respectively). The SD of fasting blood glucose (FBG), coefficient of variation of FBG, SD of blood glucose (SDBG), and mean amplitude of glycemic excursions were lower in the BOT than OADs group. Changes in the levels of three cytokines (interleukin [IL]-1β, IL-6, and IL-17α) were significantly less in the BOT than OADs group.. Twelve months of BOT decreased the incidence of DR in short-duration type 2 diabetes by reducing glycemia more effectively, stably, and completely than OADs alone.. 背景: 在本研究中, 我们比较单纯口服抗糖尿病药物(oral antidiabetic drugs, OADs)和基础胰岛素联合口服抗糖尿病药物(basal insulin-supported OADs therapy, BOT)两种治疗方案对糖尿病视网膜病变(diabetic retinopathy, DR)的影响。 方法: 本研究在2015年1月到2018年1月共入组290例糖尿病患者, 他们的年龄介于18到65岁之间, 糖尿病病程在0到5年之间。入组的患者先接受14天的胰岛素强化治疗, 然后被随机分入OAD组或者BOT组。在研究开始时和研究结束时进行相应的检查。 结果: 与OADs组相比, BOT组更少患者出现DR [BOT组8例 (6.60%) vs. OADs组12例 (8.3%)], 并且所有出现DR的患者, 其DR都属于非增殖性病变。BOT组第3个月的血糖水平较OADs组高, 但其第6个月和第12个月的血糖水平则较OADs组低。HbA1c(≤7%)的达标率, 第3个月BOT组低于OADs组(分别为63.6% 和72.2%), 第6个月两组近似(分别为60.6% 和66.6%), 第12个月BOT组高于OADs组(分别为75.0% 和61.1%)。BOT组的空腹血糖标准差、空腹血糖变异系数、血糖标准差和血糖波动平均幅度均低于OADs组。BOT组中三个细胞因子(IL-1β、IL-6和IL-17α)的变化水平显著低于OADs组。 结论: 对于病程较短的2型糖尿病患者, 12个月的BOT方案能通过更有效、平稳、全面地降低血糖而降低DR的发生率。.

Topics: Administration, Oral; Adolescent; Adult; Aged; Biomarkers; Blood Glucose; China; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incidence; Injections; Insulin Glargine; Interleukins; Male; Middle Aged; Prospective Studies; Time Factors; Treatment Outcome; Young Adult

This long-term study was designed to further characterise the retinal safety profile of insulin glargine and human neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes mellitus.. An open-label, 5 year, randomised (1:1), multicentre, stratified, parallel-group study conducted in the USA and Canada enrolled individuals with type 2 diabetes and either no or non-proliferative retinopathy (less than severe; Early Treatment Diabetic Retinopathy Study [ETDRS] level less than 53 in both eyes) who were treated with oral hypoglycaemic agents (OHAs) alone, insulin alone or OHAs with insulin for >/=3 months prior to study entry and a baseline HbA(1c) level of 6.0-12.0%. Patients were randomised by the investigator according to the centralised interactive voice response system to receive twice-daily NPH insulin (n = 509) or once-daily basal insulin glargine (n = 515). The investigator was not blinded to the treatment group to which each participant had been assigned. The main objective of this study was to compare the progression of diabetic retinopathy between treatment groups by analysing the percentage of patients with three or more step progression in the ETDRS retinopathy patient-level severity scale after treatment with either basal insulin. Masked, centralised grading of seven-field stereoscopic fundus photographs was used.. Similarly sustained glycaemic control was observed in both the insulin glargine and NPH insulin treatment groups. Despite a slightly greater severity of diabetic retinopathy for the insulin glargine group at baseline, three or more step progression in ETDRS score from baseline to end-of-study was similar between treatment groups (14.2% [53/374] of insulin glargine-treated patients vs 15.7% [57/363] of NPH-treated patients); the difference in the incidence of progression was -1.98% (95% CI -7.02, 3.06%). Other measures of retinopathy-the development of proliferative diabetic retinopathy and progression to clinically significant macular oedema-occurred to a similar degree in both treatment groups. No other safety issues, such as unexpected adverse events for either insulin emerged during the 5 year study. However, NPH insulin treatment was associated with a higher incidence of severe hypoglycaemia compared with insulin glargine.. This study shows no evidence of a greater risk of the development or progression of diabetic retinopathy with insulin glargine vs NPH insulin treatment in patients with type 2 diabetes mellitus.. ClinicalTrials.gov NCT00174824. This study was sponsored by sanofi-aventis.

Topics: Aged; Blood Glucose; Canada; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Disease Progression; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Isophane; Insulin, Long-Acting; Internationality; Male; Middle Aged; Patient Selection; United States

Topics: Diabetes Mellitus, Type 2; Diabetic Retinopathy; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Isophane; Insulin, Long-Acting; Neoplasms; Risk Factors

To establish the equivalence in efficacy (HbA(1c)) of insulin glargine injected at dinner versus bedtime in a large number of patients with type 1 diabetes using a fast-acting analogue (FAA) or regular human insulin (RHI) as prandial insulin in an insulin glargine-bolus regimen.. In a 26-week trial, 1178 patients with type 1 diabetes and treated with different basal-bolus regimens were randomized to receive insulin glargine once daily at dinner (n=589) or at bedtime (n=589) while continuing their previous prandial insulin (FAA: 75%; RHI: 25% of patients). The primary objective was to demonstrate equivalence in terms of HbA(1c) levels at endpoint.. Baseline characteristics were similar in the two groups. At endpoint, HbA(1c) (mean+/-standard deviation [S.D.]) had decreased by 0.25+/-0.66% to 7.77+/-0.96% in the dinnertime group (P<0.0001), and by 0.24+/-0.76% to 7.83+/-1.07% in the bedtime group (P<0.0001). The HbA(1c) difference between dinner and bedtime was -0.022% (two-sided 90% confidence interval [CI] -0.09; 0.05), demonstrating statistical equivalence of HbA(1c) at endpoint between the two groups. Equivalence was also demonstrated within prandial groups: HbA(1c) difference between dinner and bedtime was -0.03% (two-sided 90% CI: -0.11; 0.06) for FAAs and -0.04% (two-sided 90% CI: -0.19; 0.11) for RHIs. The incidence of severe hypoglycaemia did not differ between the treatment groups.. These data confirm that insulin glargine in combination with either FAA or RHI is equally effective and safe, whether it is administered at dinner or bedtime.

Topics: Adult; Aged; Albuminuria; Blood Glucose; Body Mass Index; Confidence Intervals; Coronary Disease; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Neuropathies; Diabetic Retinopathy; Drug Administration Schedule; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Neuritis

Early worsening of diabetic retinopathy, characterized by cotton wool spots, intraretinal microvascular abnormalities and/or macular edema, can occur following improvement of glycemic control. In four randomized 28- to 52-week clinical trials comparing insulin glargine and NPH insulin in regard to glycemic control and frequency of hypoglycemia, ophthalmologic examinations and fundus photographs were included to assess frequency of early worsening of retinopathy or other early adverse ocular effects. Retinopathy progression rates at 28 weeks were 7-12% by clinical examination and 3-8% by photographic grading; corresponding rates of clinically significant macular edema (CSME) were 1-8% and 1-4%, respectively. Optic disc swelling was not observed clinically or in photographs. Two of the 24 possible comparisons (four trials, three outcomes, two assessment methods), both of which were photographic assessments in type 2 diabetes, were in/near the nominally significant range and favored NPH insulin: 28-week rates of >or=3-step retinopathy progression (insulin glargine: 16/213, 7.5%; NPH insulin: 6/220, 2.7%; p=0.028) and 52-week CSME rates (26/233, 11.2% and 14/214, 6.5%, respectively; p=0.098). Because the between-treatment differences were small and inconsistent across trials and assessment methods, and because overall rates were consistent with the natural course of diabetic retinopathy, we conclude that it is unlikely that insulin glargine carries a higher risk of early worsening or other early adverse effect than NPH insulin. These trials tended to exclude a large early adverse effect, such as optic disc swelling, but cannot assess longer-term effects; a 5-year randomized trial of insulin glargine versus NPH insulin has been initiated. Data from this manuscript have been presented as posters and published in abstract form at the European Association for the Study of Diabetes 2001 ( DIABETOLOGIA 44(Suppl 1):I-IV(A287), 2001) and the Latin American Diabetes Association 2001 (11-15 November 2001, Punta del Este, Uruguay; Poster 180) congresses.

Topics: Adult; Aged; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Female; Fluorescein Angiography; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Isophane; Insulin, Long-Acting; Male; Middle Aged

To determine whether the use of long-acting insulin analogues is associated with an increased risk of incident diabetic retinopathy (DR) among patients with type 2 diabetes.. Using data from the Clinical Practice Research Datalink Aurum, this retrospective, population-based cohort study included patients with type 2 diabetes who initiated a long-acting insulin analogue (glargine, detemir, degludec) or Neutral Protamine Hagedorn (NPH) insulin. The primary outcome was incident DR. We used Cox proportional hazards models with inverse probability of treatment weighting to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident DR with insulin analogues versus NPH insulin.. There were 66 280 new users of long-acting insulin analogues and 66 173 new users of NPH insulin. The incidence rate of DR was 101.7 per 1000 person-years (95% CI, 98.7-104.8) for insulin analogues and 93.2 (95% CI, 90.0-96.5) per 1000 person-years for NPH insulin. Compared with the current use of NPH insulin, insulin analogues were not associated with the risk of incident DR (HR 1.04, 95% CI, 0.99-1.09). The adjusted HRs were 0.84 (95% CI, 0.66-1.07) for proliferative DR and 1.02 (95% CI, 0.97-1.08) for non-proliferative DR.. Compared with NPH insulin, long-acting insulin analogues were not associated with the risk of incident DR among patients with type 2 diabetes. This finding provides important reassurance regarding the safety of long-acting insulin analogues with respect to incident DR.

Topics: Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Isophane; Insulin, Long-Acting; Retrospective Studies

Long-acting insulin analogues were developed to facilitate consistent glycemic control without excessive hypoglycemia. However, structural modifications of the insulin molecule can alter biological responses and binding characteristics with specific receptors. The aim of this study was to estimate the risk of sight-threatening diabetic retinopathy (STDR) associated with treatment using long-acting insulin analogues compared with intermediate-acting insulin in patients with type 2 diabetes mellitus (T2DM).. A retrospective cohort consisting of patients with T2DM aged 20 years of age and older with newly initiated treatment with long-acting insulin analogues (glargine and detemir) and intermediate-acting human insulin was identified from the National Health Insurance database between January 2004 and December 2006 and was subdivided into different cohorts. The risk of the development of STDR was determined by Cox regression models and compared between different cohorts.. Of the 46,739 eligible patients, initiators of insulin glargine, insulin detemir, and neutral protamine Hagedorn (NPH) insulin were identified for comparison using propensity-score matching methods. Long-acting insulin analogues were not associated with changed risk for STDR by intention-to-treat and time-varying use approaches between either matched or unmatched cohorts.. The strategies that aim at preventing diabetic retinopathy by treating T2DM patients with long-acting insulin analogues remain further prospective studies with longer follow-up period to validate our observations within an appropriate dosage range and to further evaluate the safety of long-acting insulin analogues on reducing the progression of diabetic retinopathy.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Disease Progression; Female; Humans; Hypoglycemic Agents; Incidence; Insulin; Insulin Detemir; Insulin Glargine; Insulin, Isophane; Insulin, Long-Acting; Male; Middle Aged; Propensity Score; Retrospective Studies; Taiwan; Young Adult

Topics: Diabetes Mellitus, Type 2; Diabetic Retinopathy; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Randomized Controlled Trials as Topic

Topics: Diabetes Mellitus, Type 2; Diabetic Retinopathy; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Randomized Controlled Trials as Topic

To examine pregnancy outcome in women with Type 1 diabetes treated with glargine.. Glargine use in pregnancy was surveyed over 2 years in 20 UK obstetric-diabetes centres. Outcomes, including maternal complications, miscarriage, congenital abnormalities, perinatal morbidity and mortality, were recorded in a standardized format.. Outcomes on 109 babies from 115 women with Type 1 diabetes were collected. Insulin glargine was used prior to pregnancy in 69% of women, started during pregnancy in 30%, and stopped at booking in one patient. Insulin aspart was the bolus insulin in 45%, lispro in 42% and human soluble in 8% of women. HbA(1c) fell from 8.1 +/- 0.2% at booking to 6.8 +/- 0.1% during the third trimester. Background retinopathy developed in one patient, worsened in seven and laser photocoagulation was required in three women. Preeclampsia occurred in 12%, and 14% of women had more than one episode of severe hypoglycaemia. One hundred and nine babies were live born, with six miscarriages and no neonatal deaths. The mean gestational age was 37.5 weeks, and mean birth weight was 3500 g. Three babies had congenital abnormalities (malformation rate = 28/1000). Neonatal hypoglycaemia was seen in 46% and hyperbilirubinaemia in 22% of babies. No major adverse outcome was noted in a smaller subset of five Type 2 and seven gestational diabetes patients on glargine.. The use of glargine in Type 1 diabetes during pregnancy was not associated with any unexpected adverse maternal or fetal outcome in this study.

Topics: Abortion, Spontaneous; Adult; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Pre-Eclampsia; Pregnancy; Pregnancy in Diabetics; Pregnancy Outcome; Prospective Studies

We wanted to assess the effectiveness and safety of glargine in the treatment of patients with type 2 diabetes mellitus in secondary failure and/or with severe comorbidities ("T2DM group"), and patients with secondary diabetes after corticosteroid and/or anticancer treatment ("secondary DM group"). We reviewed the records of patients on glargine from 1 August 2004 to 30 July 2005. The after-minus-before change in HbA1c was the main outcome measure. At baseline, the 18 "T2DM" patients had a mean (+/-SD) age of 66.7+/-9.5 years and a diabetes duration of 13.6+/-10.3 years; 52.9% were male. Their fasting plasma glucose (FPG) decreased from 228.6+/-76.6 to 134.6+/-37.5, two-hour post-prandial glycaemia (2hPPG) from 268.2+/-10.4 to 140.6+/-30.8 and HbA1c from 10.4+/-2.3 to 7.9+/-1.6%. Mean daily insulin dosage was 12.0+/-4.8 UI for glargine alone and 37.4+/-22.6 UI for basal-bolus scheme. The daily cost was Euro 0.75 (range Euro 0.31-1.15). The 24 "secondary DM" patients had a mean age of 67.0+/-11.0 years and a diabetes duration of 3.7+/-6.5 years; 54.2% were male and 91.7% had a metastatic cancer. Their FPG decreased from 222.3+/-108.6 to 121.5+/-28.7 mg/dl, 2hPPG from 259.4+/-108.6 to 133.0+/-35.0 mg/dl and HbA1c from 10.1+/-2.5 to 7.6+/-1.3%. Mean daily insulin dosage was 12.5+/-6.1 UI for glargine alone and 27.2+/-9.1 UI for basal-bolus scheme. Mean daily cost was Euro 0.70 (range Euro 0.31-1.38). One (4.2%) cancer patient withdrew from glargine because of nausea. Nine (37.5%) cancer patients had an increase in appetite after glargine therapy, including 3 end-of-life patients. No severe hypoglycaemia occurred. Insulin glargine was safe and effective in improving glycaemic control both in severe "T2DM" and in "secondary DM" patients.

Topics: Adrenal Cortex Hormones; Aged; Antineoplastic Agents; Blood Glucose; Body Mass Index; Body Weight; Cardiovascular Diseases; Comorbidity; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Drug Administration Schedule; Fasting; Female; Glycated Hemoglobin; Humans; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Renal Insufficiency; Retrospective Studies; Treatment Outcome

Topics: Clinical Trials, Phase IV as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Disease Progression; Humans; Insulin; Insulin Glargine; Insulin-Like Growth Factor I; Insulin, Isophane; Insulin, Long-Acting; Retinal Diseases; Retinal Vessels; United States; United States Food and Drug Administration; Vascular Endothelial Growth Factor A