Analogues Glargine Research Articles

A randomized cross-over trial to identify the optimal use of insulin glargine in prepubertal children using a three-times daily insulin regimen.

The long-acting insulin analogue glargine reduces nocturnal hypoglycaemia and stabilizes morning blood glucose levels in patients with Type 1 diabetes (T1DM) on multiple injection therapy. However, young children may not tolerate such intensive insulin regimens. We investigated the effects of glargine in various three-injections-daily insulin combinations on 24-h glucose control in prepubertal children. Seventeen T1DM prepubertal children (10 boys), median age 10.2 years (range 6.0-12.4), glycated haemoglobin (HbA(1c)) 8.8% (6.8-11.5) were recruited to a randomized, open-label, cross-over study. After a 2-week run-in period (with NPH pre-bed), every child underwent three different 3-week treatment blocks in random order. All treatment blocks included glargine pre-bed, but used different morning insulins: block 1, soluble only; block 2, soluble + NPH; block 3, aspart + NPH. Continuous glucose monitoring was performed for 3 days at the end of the run-in and each treatment block. Compared with the run-in period on NPH, the three glargine treatment blocks were associated with lower (P < 0.0001) and less variable (P < 0.05) pre-breakfast glucose levels, and with an 8-15% reduction in total daily insulin dose (P < 0.0001). Risk of nocturnal hypoglycaemia detected by continuous glucose monitoring varied significantly between the three glargine treatment blocks, and was lowest when children were given aspart + NPH in the morning (block 3). Insulin glargine pre-bed can be used in three-injections-daily regimens in prepubertal children to lower and stabilize pre-breakfast glucose levels. However, to avoid the risk of nocturnal hypoglycaemia, the pre-bed glargine dose should be lowered by giving a further long-acting insulin, such as NPH, in the morning.

Use of insulin glargine during pregnancy

Good metabolic control maintained throughout pregnancy reduces maternal and fetal complications in diabetic women. The long-acting insulin analogue glargine has 24-h persistence and a peakless action profile, and could contribute to more stable daily plasma glucose levels and improved glycemic control. We evaluated the metabolic control associated with insulin glargine during pregnancy in comparison with conventional basal insulin therapy. Retrospective case-control analysis of glycemic control and pregnancy complications in 100 type 1 diabetic pregnancies with intermediate-acting NPH insulin or insulin glargine prior to conception and throughout pregnancy. Overall,glycemic control was not different between the groups, though the decrease in HbA1c from the first to the third trimester was greater with insulin glargine (0.8 versus 0.3%, p=0.04). The rate of hypoglycemia was comparable. Our findings suggest that, as regards metabolic control, insulin glargine in women with type 1 diabetes is comparable with NPH insulin as basal insulin therapy. No adverse effects were associated with glargine use at the time of conception and during pregnancy.

Refining basal insulin therapy: what have we learned in the age of analogues?

The basal insulin analogues glargine and detemir have been subject to a series of trials comparing their clinical profiles to the conventional preparation, neutral protamine Hagedorn (NPH). Careful review of these trials provides opportunities to learn clinically useful lessons about these insulins. MedLine-indexed trials comparing glargine or detemir to NPH were scrutinized for control, tolerability and dose data. Separate considerations were made for types 1 and 2 diabetes, and for basal-bolus and basal plus oral glucose-lowering drugs (OGLD) therapy. Attention was paid to dosing schedules and 24-h glycaemic profiles. Collectively, the trials demonstrated an improved balance between glycaemic control and tolerability for both analogues compared to NPH, regardless of regimen and diabetes type. Neither once-daily glargine nor detemir reliably provides 24-h basal insulin replacement in all patients with type 1 diabetes; a waning of effect frequently obliges twice-daily administration. When added to OGLDs in type 2 diabetes, goal-titrated once-daily basal insulin generally lowered HbA(1c) by approximately 1.5%, whereas twice-daily administration tended to increase insulin dose disproportionately to improvement in control. Hence, adding bolus insulin may be a preferable intensification method to dividing the basal dose. Varying injection time or dividing the basal insulin dose predictably affects the pattern of hypoglycaemia and bolus dose requirements. Morning administration tends to require higher dosing than evening administration. Scrutiny of trials involving glargine and detemir has increased our understanding of how best to dose basal insulins. An individualized approach is still necessary however, and several questions remain that require further research.

Prolonged glucose requirements after intentional glargine and aspart overdose

Intentional insulin overdose in diabetic patients is a rather rare critical situation. We report the case of a patient suffering from type 1 diabetes who was found comatose with a plasma glucose close to zero after having injected herself massive doses of both aspart and glargine insulin analogues. The prevention of hypoglycaemic episodes in this patient required a long-term glucose infusion (i.e., 59 hours) which significantly exceeds the usual time-effect profile of glargine. This observation emphasizes again that clinicians should be aware of the extremely prolonged action of long acting insulin analogue glargine after intentional massive injection in order to avoid a too early interruption of glucose infusion and a subsequent risk of relapse of severe hypoglycaemic episodes.

Comparison of Pharmacokinetics and Dynamics of the Long-Acting Insulin Analogs Glargine and Detemir at Steady State in Type 1 Diabetes

To compare pharmacokinetics and pharmacodynamics of insulin analogs glargine and detemir, 24 subjects with type 1 diabetes (aged 38 +/- 10 years, BMI 22.4 +/- 1.6 kg/m2, and A1C 7.2 +/- 0.7%) were studied after a 2-week treatment with either glargine or detemir once daily (randomized, double-blind, crossover study). Plasma glucose was clamped at 100 mg/dl for 24 h after subcutaneous injection of 0.35 unit/kg. The primary end point was end of action (time at which plasma glucose was >150 mg/dl). With glargine, plasma glucose remained at 103 +/- 3.6 mg/dl up to 24 h, and all subjects completed the study. Plasma glucose increased progressively after 16 h with detemir, and only eight subjects (33%) completed the study with plasma glucose <180 mg/dl. Glucose infusion rate (GIR) was similar with detemir and glargine for 12 h, after which it decreased more rapidly with detemir (P < 0.001). Estimated total insulin activity (GIR area under the curve [AUC](0-end of GIR)) was 1,412 +/- 662 and 915 +/- 225 mg/kg (glargine vs. detemir, P < 0.05), with median time of end of action at 24 and 17.5 h (glargine vs. detemir, P < 0.001). The antilipolytic action of detemir was lower than that of glargine (AUC free fatty acids(0-24 h) 11 +/- 1.7 vs. 8 +/- 2.8 mmol/l, respectively, P < 0.001). Detemir has effects similar to those of glargine during the initial 12 h after administration, but effects are lower during 12-24 h.

Diabetes: advances in treatment

The increasing prevalence of diabetes worldwide is cause for concern both in terms of associated morbidity and increasing health costs. This review aims to focus on new and emerging treatments for type 1 and type 2 diabetes. There has been recent focus on diabetes prevention both for type 1 and type 2 diabetes. Prevention programme including lifestyle measures and oral hypoglycaemic agents have shown up to 61% reduction in the development of type 2 diabetes in patients with impaired glucose tolerance or impaired fasting glucose. Little progress has been made to date on type 1 diabetes prevention although current work is focusing on T-cell immunomodulation therapy and beta cell regeneration. Management of type 2 diabetes has been improved by the recent introduction of the peroxisome proliferator-activated receptor-gamma agonists and more recently by the incretins including glucagons like peptide analogues and dipeptidyl peptidase-4 inhibitors. This article focuses on the benefits and restrictions of these new agents. The new insulin analogues glargine and detemir have made significant improvements in the management of type 1 diabetes both in terms of improvement in glycaemic control and in reducing hypoglycaemia rates. Inhaled insulin also shows promise for needle-free treatment of diabetes and these insulins are currently undergoing phase 3 trials. Insulin infusion pumps are becoming more sophisticated and increasingly popular in the management of type 1 diabetes. Many studies have shown benefits for improved glycaemic control and reduced rates of hypoglycaemia with pump treatment compared with multiple daily injections. Pancreas and islet cell transplantation are the subject of ongoing research, but currently require immunosuppressive treatment regimes. The main limitation is lack of availability of donor pancreases. There is much hope that new treatments outlined in this review will result in improved outcomes in the treatment of diabetes.

No Apparent Alteration of F-18 FDG Biodistribution When Injected Shortly After Insulin Glargine

Abstract: F-18 FDG PET scans acquired after insulin administration usually show prominent skeletal and cardiac muscle FDG uptake, which may hinder accurate scan interpretation. We performed an FDG PET/CT scan on a 25-year-old diabetic woman who received the long-acting insulin analog glargine (Lantus; Sanofi-Aventis) 3 hours before FDG injection. The scan showed no significant alteration of FDG biodistribution. Insulin glargine has no pronounced peak over 24 hours and is being used more frequently to create basal insulin level in patients with type 1 and type 2 diabetes. Our findings suggest that insulin glargine may not need to be withheld prior to PET scintigraphy.

Pharmacokinetics and Pharmacodynamics of the Long-Acting Insulin Analog Glargine After 1 Week of Use Compared With Its First Administration in Subjects With Type 1 Diabetes

Pharmacokinetics and pharmacodynamics of the long-acting insulin analog glargine (1) are superior to those of insulin NPH (2–9). In the clinical setting, this translates into lower risk of nocturnal hypoglycemia (10–13), lower A1C (provided that appropriate requirements of mealtime rapid-acting insulin are met) (11–13), and the convenience of once (12), compared with multiple, administration of NPH (14). However, no study has examined subjects after several days of its use versus the “first” subcutaneous injection. The present studies were undertaken to establish the pharmacokinetics and pharmacodynamics of insulin glargine in type 1 diabetes after 1 week of its once-daily use and to compare it with those observed after the first injection. After institutional review board approval, 20 type 1 diabetic subjects (12 male subjects, age 31 ± 2 years, type 1 diabetes duration 11 ± 1 years, BMI 23.3 ± 0.4 kg/m2, fasting plasma C-peptide <0.02 nmol/l, and A1C 7.1 ± 0.2%) using NPH as basal insulin and human regular insulin ( n = 7) or lispro insulin ( n = 13), in combination with NPH at each meal as previously described (14), were studied. During a 2-week run-in period, subjects continued their previous model of insulin therapy, i.e., human regular insulin or the rapid-acting insulin analog lispro at breakfast, lunch, and dinner and NPH insulin at bedtime, or even at each meal in those patients ( n = 13) who used lispro (14). Thereafter, subjects were studied with the glucose clamp technique after subcutaneous injection of 0.3 units/kg insulin glargine as previously described (6). Subjects …

Comparison of the Mitogenic Potency of Regular Human Insulin and its Analogue Glargine in Normal and Transformed Human Breast Epithelial Cells

Comparison of the Mitogenic Potency of Regular Human Insulin and its Analogue Glargine in Normal and Transformed Human Breast Epithelial Cells

Usefulness of the Long-acting Insulin Analogue Glargine in Basal-Bolus Therapy for Japanese Children and Adolescents with Type 1 Diabetes Mellitus

The aim of this study was to evaluate the efficacy of long-acting insulin analogue glargine (G) changing from NPH in basal-bolus therapy for Japanese children and adolescents with type 1 diabetes mellitus (DM1). Thirty patients (11 M, 19 F) with DM1 aged 13.3 +/- 4.5 years were included in the study. Mean fasting blood glucose level was significantly decreased (baseline: 142.5 +/- 39.3 vs 127.1 +/- 24.0, 129.0 +/- 29.1, 121.1 +/- 26.0 mg/dl at 3, 6, 12 months, respectively, p <0.01), and mean HbA(1c) was significantly decreased (baseline: 8.06 +/- 0.85 vs 7.69 +/- 0.89, 7.57 +/- 0.93, 7.36 +/- 0.95%, at 3, 6, 12 months, respectively, p <0.01) after changing to G from NPH. Severe hypoglycemia rarely occurred during the study period. In conclusion, basal-bolus therapy using G resulted in improved overall glycemic control with a low risk of severe hypoglycemia in Japanese pediatric patients with DM1.

The insulin analog glargine during an unplanned pregnancy

The insulin analog glargine during an unplanned pregnancy

Treatment with insulin glargine does not suppress serum IGF‐1

A 6-8-fold higher insulin-like growth factor 1 (IGF-1) receptor binding affinity in vitro is reported for the insulin analogue glargine compared with human insulin. This study evaluates the in vivo significance by exploring the growth hormone (GH)-IGF-1 axis. Assuming a higher binding affinity of insulin glargine to pituitary IGF-1 receptors, serum IGF-1 concentrations should decrease via negative feedback. In a crossover study, insulin glargine or NPH insulin, respectively, were used in identical doses as basal insulins in treatment periods of 3 weeks. Overall glycaemic control was not different between the treatment regimens. In contrast to the hypothesis, serum IGF-1 concentrations were higher during insulin glargine treatment compared with NPH insulin in patients with Type 1 diabetes (177 +/- 18 vs. 159 +/- 18 microg/l, P < 0.02, n = 17, age 28 +/- 2 years). The effect on IGF-1 was most pronounced in male patients with Type 1 diabetes (174 +/- 11 vs. 146 +/- 10 microg/l, P < 0.02, n = 10), but was not significant in patients with Type 2 diabetes (92 +/- 9 vs. 86 +/- 8 microg/l, NS, n = 25, age 66 +/- 2 years). In contrast to our hypothesis, serum IGF-1 did not decrease, but rose during insulin glargine treatment, suggesting an absence of relevant IGF-1-like activity of glargine at the level of the pituitary. Improved plasma glucose at dawn during glargine treatment may intensify growth hormone surges and increase IGF-1 synthesis. Significant increases were seen in younger patients, compatible with the higher activity of the GH-IGF-1 axis in this age group.

Intensive insulin therapy today: ‘basal-bolus’ using multiple daily injections or CSII?

Intensive insulin therapy aiming at normoglycemia in order to prevent long-term complications is not questionable for the management of type 1 diabetes mellitus nowadays. The gold standard mode of insulin therapy in this view is CSII using fast-acting analogues. Whether this reference method can be challenged by MDI using recently available long- and fast-acting analogues remains an open question. Use of fast-acting analogues provides similar benefits on post-meal glucose control either by MDI or by CSII. Long-acting analogues glargine and detemir have shown better effectiveness on basal blood glucose control, including improved stability and reduced occurrence of hypoglycemic episodes, than NPH and ultralente. Reported comparisons between CSII and MDI using glargine have been limited until now. While some of them have shown that CSII allowed both lower HbA1(c) and incidence of hypoglycemia, similar effects have been obtained in other experiences. From present data, it appears that CSII remains the most effective mode of intensive insulin therapy although it may be challenged in patients with stable basal insulin needs. Nevertheless, individual factors seem to be decisional in the choice between CSII and MDI using long-acting analogues, among which patient ability and will to use an insulin pump are critical.

Insulin and its analogue glargine do not affect viability and proliferation of human coronary artery endothelial and smooth muscle cells

Present guidelines for the treatment of type 2 diabetes recommend HbA1c values of less than 7%. As beta cell function worsens during progress of the disease, insulin therapy is often necessary to achieve this ambitious goal. However, due to peripheral insulin resistance, many patients need rather high insulin dosages. In the light of the extremely high cardiovascular risk of diabetic patients, it is important to determine whether high concentrations of insulin or its frequently used analogues are harmful to the cardiovascular system. We therefore investigated the modulatory effects of regular human insulin and its analogue glargine on proliferation and apoptosis of human coronary artery endothelial cells (HCAECs) and human coronary artery smooth muscle cells (HCASMCs). Cells were treated with regular human insulin or insulin glargine. Proliferation was determined by [3H]thymidine incorporation and by flow cytometric analysis of Ki-67 expression. Apoptosis was assessed by flow cytometry (cell cycle analysis and annexin V staining) and determination of caspase-3 activity. HCAECs and HCASMCs treated with regular human insulin or insulin glargine did not show significant increases in DNA synthesis or Ki-67 expression. Administration of regular human insulin or insulin glargine did not modulate the extent of apoptotic events. No influence of insulin on lipoapoptotic vascular cell death could be detected. Taken together, neither regular human insulin nor insulin glargine influences growth and apoptosis of human coronary artery cells in vitro. Our data do not suggest that regular human insulin or insulin glargine promote atherosclerosis through mechanisms affecting the cellularity of human coronary arteries.

Use of Insulin Glargine During the First Weeks of Pregnancy in Five Type 1 Diabetic Women

The long-acting analog glargine is a new insulin with 24-h persistence. This peculiar peakless action profile accounts for significant risk reduction for nocturnal hypoglycemia and a more stable daily plasma glucose profile (1,2). Only a few reports have described the use of insulin glargine during human pregnancy, so its use is not recommended at present. Animal studies have addressed the safety and efficacy of glargine during pregnancy, showing no direct effect on reproduction and embryo-fetal development (3 ) . Recently, Devlin et al. (4) and Holstein et al. (5) reported the use of insulin glargine in two type 1 diabetic women; both cases were free of any pregnancy complications and …

Differences in hypoglycemia event rates and associated cost-consequence in patients initiated on long-acting and intermediate-acting insulin products

ABSTRACTObjective: To compare hypoglycemia event rates in patients initiated on long-acting insulin analog (glargine) or intermediate-acting insulin (NPH) and to analyze the associated cost-consequence from a managed care perspective.Study design: A retrospective analysis of pharmacy and medical claims and electronic laboratory result data using a southeastern United States managed care health plan.Methods: Patients newly initiated on glargine or NPH between July 1, 2000 and August 31, 2002 were included. Hypoglycemia events were identified from medical claims by their ICD-9-CM codes. Multivariable techniques were used to compare hypoglycemia event rates between cohorts.Results: A total of 1434 patients were eligible (glargine = 310, NPH = 1124). The mean age was 53 years ± 17 years and 51% of patients were male. The mean treatment duration was 8.6 months ± 4.5 months. Multivariate analyses showed that patients in the NPH group had a higher hypoglycemia event rate than the glargine group (18.3 versus 7.3 per 100 patients per year; p = 0.009). The number needed to treat (glargine versus NPH) to avoid one hypoglycemia event per patient per year was nine patients at an A1C of 7%. The mean annual index medication cost was $47 more for glargine ($390) than for NPH ($343) per patient per year ( p = 0.042). The mean cost per hypoglycemia event was $1087 (95% CI: $764–$1409).Conclusions: Patients treated with glargine had significantly lower hypoglycemia event rates compared to the NPH group. The risk difference indicated that one hypoglycemia event would be avoided for every nine patients treated with glargine instead of NPH. The cost increase associated with treating nine patients with glargine rather than NPH is less than the cost of treating one hypoglycemia event. In this population, the savings associated with reduced hypoglycemic events more than offset the increased acquisition cost associated with glargine.

Experimental Autoimmune Diabetes: A New Tool to Study Mechanisms and Consequences of Insulin‐Specific Autoimmunity

(Prepro)insulin is considered a central antigenic determinant in diabetic autoimmunity. Insulin has been used to modify diabetes development in NOD mice and prediabetic individuals. We have recently shown that (prepro)insulin can adversely promote diabetes development in murine type 1 diabetes. Based on these findings we have developed experimental autoimmune diabetes (EAD), a new mouse model characterized by (1) CD4(+)/CD8(+) insulitis, induced by (2) (prepro)insulin DNA vaccination, leading to (3) beta cell damage and insulin deficiency in (4) RIP-B7.1 transgenic mice (H-2(b)). EAD develops rapidly in 60-95% of mice after intramuscular, but not intradermal ("gene gun"), vaccination; and DNA plasmids expressing insulin or the insulin analogues glargine, aspart, and lispro are equally potent to induce EAD. Similar to NOD mice, diabetes is adoptively transferred into syngeneic recipients by spleen cell transplantation in a dose-dependent fashion. We have devised a two-stage concept of EAD in which T cell activation and expansion is driven by in vivo autoantigen expression, followed by islet damage that requires beta cell expression of costimulatory B7.1 for disease manifestation. Taken together, EAD is a novel, genetically defined animal model of type 1 diabetes suitable to analyze mechanisms and consequences of insulin-specific T cell autoimmunity.

Treatment of patients with severe insulin deficiency: what we have learned over the past 2 years

The initial injection in 1922 of a pancreatic extract, or insulin as it came to be known, into a patient with diabetes mellitus has since been followed by the successive introduction of longer-acting insulins, more highly purified insulins, and insulins that have been modified to more closely match insulin activity to patients' physiologic requirements. The recently introduced rapid-acting insulin analogues lispro and aspart and the long-acting analogue glargine are further refinements of insulin therapy. Current treatment strategies for severe insulin deficiency are based on the need to provide 2 components of insulin replacement: basal and postprandial. Rapid-acting insulin has been shown to provide superior postprandial glucose control compared with regular insulin. Truly effective control of basal insulin has been achieved by the introduction of the insulin pump in the 1980s and insulin glargine in 2001. Insulin glargine is the first insulin analogue to provide, in a majority of patients, a continuous level of insulin without a pronounced peak after a single daily injection, closely mimicking the normal pancreatic release of basal insulin in healthy individuals. Clinical experience is providing many insights into how basal and prandial components of insulin therapy can be best combined, although evidence from controlled trials will take some years to accumulate. Experience and observations since 2001 indicate that insulin therapy should be introduced earlier in patients with type 2 diabetes to control blood glucose levels. More importantly, the greatest benefit of insulin glargine has been to change positively the way physicians and patients think about insulin therapy. Newer insulin analogues, improved devices for home glucose monitoring, and pulmonary inhaled insulin are other innovations that promise improvement of hemoglobin A 1c levels.

Insulin-like growth factor I receptors are more abundant than insulin receptors in human micro- and macrovascular endothelial cells.

Micro- and macroangiopathy are major causes of morbidity and mortality in patients with diabetes. Our aim was to characterize IGF-I receptor (IGF-IR) and insulin receptor (IR) in human micro- and macrovascular endothelial cells. Cultured human dermal microvascular endothelial cells (HMVEC) and human aortic endothelial cells (HAEC) were used. Gene expression was measured by quantitative real-time RT-PCR and receptor protein by ligand-binding assay. Phosphorylation of IGF-IR beta-subunit was analyzed by immunoprecipitation and Western blot. Glucose metabolism and DNA synthesis was assessed using [(3)H]glucose and [(3)H]thymidine incorporation, respectively. We detected gene expression of IGF-IR and IR in HAEC and HMVEC. IGF-IR gene expression was severalfold higher than that of IR. The specific binding of (125)I-IGF-I was higher than that of (125)I-insulin in HAEC and HMVEC. Insulin and the new, long-acting insulin analog glargine interacted with the IGF-IR with thousand- and hundred-fold less potency than IGF-I itself. Phosphorylation of the IGF-IR beta-subunit was shown in HAEC for IGF-I (10(-8) M) and insulin (10(-6) M) and in HMVEC for IGF-I and glargine (10(-8) M, 10(-6) M). IGF-I 10(-7) M stimulated incorporation of [(3)H]thymidine into DNA, and 10(-9)-10(-7) M also the incorporation of [(3)H]glucose in HMVEC, whereas glargine and insulin had no significant effects at 10(-9)-10(-7) M. Human micro- and macrovascular endothelial cells express more IGF-IR than IR. IGF-I and high concentrations of glargine and insulin activates the IGF-IR. Glargine has a higher affinity than insulin for the IGF-IR but probably has no effect on DNA synthesis at concentrations reached in vivo.

Evolving approaches to intensive insulin therapy in type 1 diabetes: multiple daily injections, insulin pumps and new methods of monitoring.

Ke yW ords. intensive insulin therapy, multiple daily injections, basal-bolus therapy, continuous subcutaneous insulin infusion Type 1 diabetes affects approximately 1 million individuals in the United States, whose management has significantly changed over the last decades. Initially, following the discovery of insulin in the early 1920’s, improvements centered around the purification of insulin formulations. Later came the development of both shortand longer-acting insulin preparations and more recently the availability of the insulin analogues aspart, lispro and glargine, which have added to our ability to deliver physiologic insulin replacement patterns. However, insulin is only one component of therapy. Another critical element has been the development of devices for selfmonitoring blood glucose (SMBG). As these devices have become increasingly accurate and convenient, they have allowed patients to monitor blood glucose more often and accurately, adding a critical component to diabetes management. Much of the impetus to develop better therapies for the management of type 1 diabetes stems from an understanding of the importance of blood glucose control. The association between glycemic control and microvascular complications was established with the publication in 1993 of results from the Diabetes Control and Complications Trial (DCCT), the landmark study which demonstrated the benefit of efforts to achieve excellent glucose control to limit retinopathy and nephropathy [1]. Establishment of this relationship has led to significant changes in management. In this review we will discuss the concepts behind the current management of type 1 diabetes, beginning with a definition of intensive insulin therapy, and the various ways by which it can be achieved. We will then discuss the elements involved in intensive therapy, including essential educational components, glucose monitoring, and the newer monitoring devices that are available.