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M Davis - One of the best experts on this subject based on the ideXlab platform.
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similar progression of diabetic retinopathy with Insulin glargine and neutral protamine hagedorn NPH Insulin in patients with type 2 diabetes a long term randomised open label study reply to chantelau e letter and currie cj letter
Diabetologia, 2009Co-Authors: Julio Rosenstock, Vivian Fonseca, Janet B Mcgill, Matthew C Riddle, J P Halle, Irene Hramiak, P Johnston, M DavisAbstract:To the Editor: We thank Dr E. Chantelau and Dr C. Currie for their interest [1, 2] in our findings [3], which we consider important because they are from a long-term randomised study that avoids the many limitations of retrospective database registry studies. They mainly commented on the power of the study and the possibility of performing post hoc sub-analyses. We would like to address their assertions, which we believe to be incorrect or misleading. We strongly disagree with Dr Chantelau’s suggestion that the study was underpowered to detect changes in the rate of progression of diabetic retinopathy (DR) [1]. The sample size and power for the study were calculated based on these assumptions: a 20% 5 year background event rate; a non-inferiority margin of 10% (i.e. 50% of the background rate of 20%); approximately 60% of the randomised participants evaluable; and the two treatments being equivalent. Statistical power considerations are only relevant during the study planning stage, to arrive at the sample size. On completion, the non-inferiority hypothesis will either be accepted or rejected, depending on the actual outcome observed, and the pre-study power assumption is no longer relevant. Nevertheless, had a 5 year background event rate of 15% been projected (our observed rates were 14.2% and 15.7% in the Insulin glargine [A21Gly,B31Arg,B32Arg human Insulin] and neutral protamine Hagedorn [NPH] Insulin groups, respectively), with a non-inferiority margin of 7.5% (i.e. 50% of the background 15% rate) and a sample size that is the same as that of the per protocol population, the study would have had 81% power to demonstrate equivalence. Hence, the study was not underpowered. Dr Chantelau also questioned the low frequency of DR at study entry (15.6% and 12.1% of patients reporting a medical history of DR in the Insulin glargine and the NPH Insulin groups, respectively; Table 1 of [3]), and objected to pooling patients with and without DR at baseline in assessing progression. Regarding the baseline prevalence of DR, Table 1 of our paper [3] also shows the frequency of DR based on grading of the baseline fundus photographs. By using this more sensitive measurement, a substantial proportion of patients were shown to have DR (~61% in both groups). Pooling patients with no DR and those with non-proliferative DR is appropriate when analysing, as we did, the prevalence of worsening by at least three steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) retinopathy severity scale. To illustrate this, in the DCCT, this outcome was observed at 6 years in the primary prevention cohort (no DR) in 35% and 11% of the conventional and intensive treatment groups, respectively. The corresponding rates in the secondary prevention cohort (mild to moderate non-proliferative DR) were similar—31% and 11%, respectively [4]. In a subset of 1919 UK Prospective Diabetes Study (UKPDS) patients with appropriate photographs, the 6 year prevalence of worsening by three steps or more was 17.4% in 1216 patients without DR at baseline and 18.5% in 701 patients with non-proliferative DR [5]. Dr Currie [2] questions the selection of the patient population and the exclusion of established proliferative DR in the study, comments on the protective effects of metformin against cancer, proposes multiple arbitrary post hoc subgroup analyses, and notes that Insulin glargine and NPH Insulin resulted in similar glycaemic control. We believe that the population selected is indeed the population that should be studied, as it represents the majority of patients with type 2 diabetes treated with Insulin who are seen in clinical practice. The entrance criteria allowed inclusion of a wide range of patients previously treated with human basal Insulin, with or without regular Insulin and oral agents; the resulting population closely matches that seen in clinical practice. The entry criteria did specify a particular range of DR, to assure a population in which assessment of the primary outcome would be most effective. The observed event rate for progression of three or more steps in ETDRS score in this study was ~15% at 5 years [3], and was similar to the rates in the UKPDS and DCCT [4, 5], as described above. Therefore, the suggestion that ‘… these patients could be those patients least likely to develop more severe visual loss ...’ is incorrect. Inclusion of patients with advanced forms of DR to assess progression, as Dr Currie suggested, is highly unreliable. In this study, no statistically significant difference in the development of proliferative DR was observed between the two groups, despite a greater frequency of the highest category of non-proliferative DR—in which progression of proliferative DR is most likely—at entry in the Insulin glargine group. The comparison of our randomised trial with a retrospective analysis on metformin and cancer is inappropriate. The percentage of patients using metformin was similar in both groups in this study (41% at baseline in the glargine group vs 42% with NPH, and 18% started after randomisation in the glargine group vs 16% with NPH) [3]; therefore, an imbalance of the effects of metformin could not have contributed to the findings. Furthermore, the publication authored by Currie et al. [6] and cited in his letter [2] actually demonstrated no increase in the frequency of cancer with Insulin glargine compared with other Insulins. There is no basis for Dr Currie’s speculative statement that ‘Akin to the safety issue with respect to cancer, it could be that Insulin glargine does not trigger the [retinal] pathology, but, rather, promotes or accelerates the pathological process.’ Moreover, the question of the potential protective effects of metformin against cancer is difficult to evaluate in epidemiological analyses such as the ones Dr Currie cites, because of the tendency for metformin to be prescribed for younger and healthier patients. Regarding cancer risk with different Insulins, our study is particularly relevant as it is the only randomised study to compare Insulin glargine with human Insulin, and because it shows no trend towards a greater risk of neoplasia with Insulin glargine [7]. Recently published expert statements and objective criticisms have highlighted the possibilities for bias inherent in epidemiological, non-randomised comparisons of treatments [8–10]. The multiple subgroup analyses suggested by Dr Currie seem ill-advised for a randomised trial, in that (1) the diminished sample sizes of the subsets, with consequently much wider confidence intervals for statistical testing, weaken the conclusions that can be drawn; and (2) multiple post hoc analyses increase the chance of ‘uncovering’ findings that are statistically significant but spurious. Such post hoc sub-analyses can generate hypotheses, but neither provide final answers nor put to bed any lingering concerns. Dr Currie notes that the slightly higher level of HbA1c observed with Insulin glargine compared with NPH Insulin was not emphasised in the paper. The study design clearly states the retinal primary objective and emphasises that testing differences in glycaemic control between the two Insulins was not one of the study objectives. The intention was for glycaemic control to be as similar as possible in the two groups, despite Insulin glargine being given once daily and NPH Insulin twice daily, to avoid confounding the interpretation of the retinal outcomes. The requirement that NPH Insulin be given twice daily vs once daily for Insulin glargine actually provides a bias in favour of NPH Insulin in titration of dosage. The small difference (0.2%) at study end in favour of NPH Insulin is, therefore, not surprising. In any case, the upper bound of the two-sided 95% confidence interval for HbA1c treatment difference was 0.35%, which is within the non-inferiority margin of 0.4% conventionally accepted as a basis for clinical equivalence in efficacy of HbA1c between two treatments. This difference may be important mainly in strengthening the finding that retinopathy was not adversely affected by use of Insulin glargine vs NPH Insulin, despite slightly higher mean glucose. Finally, concerning hypoglycaemia, this study confirms findings from many other studies, which have consistently found a lower incidence of hypoglycaemia with Insulin glargine treatment than with NPH Insulin with otherwise similar regimens and at similar levels of glycaemic control [11–18]. In summary, we believe that the assertions made in these two letters are speculative and misguided. Our findings and conclusions are based on the largest and longest randomised trial comparing two types of Insulin. The study design was appropriate to address concerns about the effects that Insulin glargine might have on the progression of diabetic retinopathy, and the conclusions are well supported. We are confident that the reassuring findings and conclusions are correct as reported.
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similar risk of malignancy with Insulin glargine and neutral protamine hagedorn NPH Insulin in patients with type 2 diabetes findings from a 5 year randomised open label study
Diabetologia, 2009Co-Authors: Julio Rosenstock, Vivian Fonseca, Janet B Mcgill, Matthew C Riddle, J P Halle, Irene Hramiak, P Johnston, M DavisAbstract:To the Editor: We have reported a randomised, long-term safety study comparing the effects of using the Insulin analogue glargine (A21Gly,B31Arg,B32Arg human Insulin) versus human neutral protamine Hagedorn (NPH) Insulin for 5 years in the management of type 2 diabetes [1]. The study, in which 1017 patients were randomised and treated, was designed to assess ocular complications of diabetes: there was no excess of such effects with Insulin glargine compared with NPH Insulin treatment and there was a similar slow progression of diabetic retinopathy with both types of Insulin. Because of recent concerns about postulated neoplastic effects of Insulins [2–5], we report here additional information from our study that bears on this question. In total, the mean cumulative exposure in our study was more than 4 years (1,524 days in the Insulin glargine group and 1,522 days in the NPH Insulin group), with more than 70% of patients exposed to more than 4 years of treatment (76% and 71%, respectively) (Table 1). Table 1 Summary of extent of exposure (safety population) The baseline demographics and diabetes status were similar between the two treatment groups (Insulin glargine vs NPH Insulin): diabetes duration (10.7 vs 10.8 years), BMI (34.5 vs 34.1 kg/m2), oral hypoglycaemic agent duration (9.0 vs 8.9 years), prior Insulin use (67% vs 70%), HbA1c (8.4% vs 8.3%) and fasting plasma glucose (10.5 vs 10.0 mmol/l). Although the study was not designed to investigate the frequency of tumour development, the long duration of the trial enables a comparative assessment of the occurrence of benign or malignant tumours with Insulin glargine and NPH Insulin during more than 4 years of exposure, captured as adverse events in the course of routine safety monitoring. The number of patients with treatment-emergent adverse events (defined as events that first occurred or worsened after randomisation) of neoplasm, summarised by System Organ Class and High-level Group Term levels using the standard Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary (version 10.0; Maintenance and Support Services Organization, Chantilly, VA, USA) [6], are shown in Table 2. Benign and malignant tumours reported by the investigators, along with those of unspecified pathology, are included. A more detailed listing of MedDRA-coded neoplasms is available [7]. Table 2 Patients with neoplasms reported as treatment-emergent adverse events The overall number of patients with neoplasms (using the standard MedDRA coding dictionary) occurring during the trial was similar in the two treatment groups: 57 patients (11.1%) in the Insulin glargine group vs 62 patients (12.3%) in the NPH Insulin group, with an RR for Insulin glargine of 0.90 (95% CI 0.64–1.26). In addition, when only the number of patients with malignant neoplasms reported as serious treatment-emergent events was captured, the rate was also similar in both treatment groups: 20 patients (3.9%) with 23 events in the Insulin glargine group vs 31 patients (6.2%) with 32 events in the NPH Insulin group, with an RR for Insulin glargine of 0.63 (95% CI 0.36–1.09). The number of patients with malignant breast tumours reported was also similar between the two treatment groups: three patients in the Insulin glargine group (all reported as serious) compared with five patients (four reported as serious) in the NPH Insulin group. The RR estimate of all malignant breast tumour cases, including non-serious cases (three in the Insulin glargine group vs five in the NPH Insulin group) numerically favours Insulin glargine (RR 0.59, 95% CI 0.14–2.44). Although the 95% CI includes 2, it must be noted that due to the small numbers of patients and the small number of cases, there was only a 22% power to reject a doubling in the risk (RR 2.0) of developing this tumour, should the true risks be equal. Considering all neoplasms (RR 0.9) and all malignant neoplasms (RR 0.63), the results numerically favour Insulin glargine with 95% upper CI limits of 1.26 and 1.09, respectively, indicating at most a 26% and 9% increase in risk. In summary, this study is the longest controlled treatment comparison of Insulin glargine versus NPH Insulin in patients with type 2 diabetes mellitus. No new safety issues emerged for either Insulin studied based on the data from this 5 year trial. Additional data reported here also confirm that there was no evidence of any difference in the rate of benign or malignant tumour development with Insulin glargine compared with NPH Insulin.
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similar progression of diabetic retinopathy with Insulin glargine and neutral protamine hagedorn NPH Insulin in patients with type 2 diabetes a long term randomised open label study
Diabetologia, 2009Co-Authors: Julio Rosenstock, Vivian Fonseca, Janet B Mcgill, Matthew C Riddle, J P Halle, Irene Hramiak, P Johnston, M DavisAbstract:Aims/hypothesis 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. Methods 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 HbA1c 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 patientlevel severity scale after treatment with either basal Insulin. Masked, centralised grading of seven-field stereoscopic fundus photographs was used.
Julio Rosenstock - One of the best experts on this subject based on the ideXlab platform.
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similar progression of diabetic retinopathy with Insulin glargine and neutral protamine hagedorn NPH Insulin in patients with type 2 diabetes a long term randomised open label study reply to chantelau e letter and currie cj letter
Diabetologia, 2009Co-Authors: Julio Rosenstock, Vivian Fonseca, Janet B Mcgill, Matthew C Riddle, J P Halle, Irene Hramiak, P Johnston, M DavisAbstract:To the Editor: We thank Dr E. Chantelau and Dr C. Currie for their interest [1, 2] in our findings [3], which we consider important because they are from a long-term randomised study that avoids the many limitations of retrospective database registry studies. They mainly commented on the power of the study and the possibility of performing post hoc sub-analyses. We would like to address their assertions, which we believe to be incorrect or misleading. We strongly disagree with Dr Chantelau’s suggestion that the study was underpowered to detect changes in the rate of progression of diabetic retinopathy (DR) [1]. The sample size and power for the study were calculated based on these assumptions: a 20% 5 year background event rate; a non-inferiority margin of 10% (i.e. 50% of the background rate of 20%); approximately 60% of the randomised participants evaluable; and the two treatments being equivalent. Statistical power considerations are only relevant during the study planning stage, to arrive at the sample size. On completion, the non-inferiority hypothesis will either be accepted or rejected, depending on the actual outcome observed, and the pre-study power assumption is no longer relevant. Nevertheless, had a 5 year background event rate of 15% been projected (our observed rates were 14.2% and 15.7% in the Insulin glargine [A21Gly,B31Arg,B32Arg human Insulin] and neutral protamine Hagedorn [NPH] Insulin groups, respectively), with a non-inferiority margin of 7.5% (i.e. 50% of the background 15% rate) and a sample size that is the same as that of the per protocol population, the study would have had 81% power to demonstrate equivalence. Hence, the study was not underpowered. Dr Chantelau also questioned the low frequency of DR at study entry (15.6% and 12.1% of patients reporting a medical history of DR in the Insulin glargine and the NPH Insulin groups, respectively; Table 1 of [3]), and objected to pooling patients with and without DR at baseline in assessing progression. Regarding the baseline prevalence of DR, Table 1 of our paper [3] also shows the frequency of DR based on grading of the baseline fundus photographs. By using this more sensitive measurement, a substantial proportion of patients were shown to have DR (~61% in both groups). Pooling patients with no DR and those with non-proliferative DR is appropriate when analysing, as we did, the prevalence of worsening by at least three steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) retinopathy severity scale. To illustrate this, in the DCCT, this outcome was observed at 6 years in the primary prevention cohort (no DR) in 35% and 11% of the conventional and intensive treatment groups, respectively. The corresponding rates in the secondary prevention cohort (mild to moderate non-proliferative DR) were similar—31% and 11%, respectively [4]. In a subset of 1919 UK Prospective Diabetes Study (UKPDS) patients with appropriate photographs, the 6 year prevalence of worsening by three steps or more was 17.4% in 1216 patients without DR at baseline and 18.5% in 701 patients with non-proliferative DR [5]. Dr Currie [2] questions the selection of the patient population and the exclusion of established proliferative DR in the study, comments on the protective effects of metformin against cancer, proposes multiple arbitrary post hoc subgroup analyses, and notes that Insulin glargine and NPH Insulin resulted in similar glycaemic control. We believe that the population selected is indeed the population that should be studied, as it represents the majority of patients with type 2 diabetes treated with Insulin who are seen in clinical practice. The entrance criteria allowed inclusion of a wide range of patients previously treated with human basal Insulin, with or without regular Insulin and oral agents; the resulting population closely matches that seen in clinical practice. The entry criteria did specify a particular range of DR, to assure a population in which assessment of the primary outcome would be most effective. The observed event rate for progression of three or more steps in ETDRS score in this study was ~15% at 5 years [3], and was similar to the rates in the UKPDS and DCCT [4, 5], as described above. Therefore, the suggestion that ‘… these patients could be those patients least likely to develop more severe visual loss ...’ is incorrect. Inclusion of patients with advanced forms of DR to assess progression, as Dr Currie suggested, is highly unreliable. In this study, no statistically significant difference in the development of proliferative DR was observed between the two groups, despite a greater frequency of the highest category of non-proliferative DR—in which progression of proliferative DR is most likely—at entry in the Insulin glargine group. The comparison of our randomised trial with a retrospective analysis on metformin and cancer is inappropriate. The percentage of patients using metformin was similar in both groups in this study (41% at baseline in the glargine group vs 42% with NPH, and 18% started after randomisation in the glargine group vs 16% with NPH) [3]; therefore, an imbalance of the effects of metformin could not have contributed to the findings. Furthermore, the publication authored by Currie et al. [6] and cited in his letter [2] actually demonstrated no increase in the frequency of cancer with Insulin glargine compared with other Insulins. There is no basis for Dr Currie’s speculative statement that ‘Akin to the safety issue with respect to cancer, it could be that Insulin glargine does not trigger the [retinal] pathology, but, rather, promotes or accelerates the pathological process.’ Moreover, the question of the potential protective effects of metformin against cancer is difficult to evaluate in epidemiological analyses such as the ones Dr Currie cites, because of the tendency for metformin to be prescribed for younger and healthier patients. Regarding cancer risk with different Insulins, our study is particularly relevant as it is the only randomised study to compare Insulin glargine with human Insulin, and because it shows no trend towards a greater risk of neoplasia with Insulin glargine [7]. Recently published expert statements and objective criticisms have highlighted the possibilities for bias inherent in epidemiological, non-randomised comparisons of treatments [8–10]. The multiple subgroup analyses suggested by Dr Currie seem ill-advised for a randomised trial, in that (1) the diminished sample sizes of the subsets, with consequently much wider confidence intervals for statistical testing, weaken the conclusions that can be drawn; and (2) multiple post hoc analyses increase the chance of ‘uncovering’ findings that are statistically significant but spurious. Such post hoc sub-analyses can generate hypotheses, but neither provide final answers nor put to bed any lingering concerns. Dr Currie notes that the slightly higher level of HbA1c observed with Insulin glargine compared with NPH Insulin was not emphasised in the paper. The study design clearly states the retinal primary objective and emphasises that testing differences in glycaemic control between the two Insulins was not one of the study objectives. The intention was for glycaemic control to be as similar as possible in the two groups, despite Insulin glargine being given once daily and NPH Insulin twice daily, to avoid confounding the interpretation of the retinal outcomes. The requirement that NPH Insulin be given twice daily vs once daily for Insulin glargine actually provides a bias in favour of NPH Insulin in titration of dosage. The small difference (0.2%) at study end in favour of NPH Insulin is, therefore, not surprising. In any case, the upper bound of the two-sided 95% confidence interval for HbA1c treatment difference was 0.35%, which is within the non-inferiority margin of 0.4% conventionally accepted as a basis for clinical equivalence in efficacy of HbA1c between two treatments. This difference may be important mainly in strengthening the finding that retinopathy was not adversely affected by use of Insulin glargine vs NPH Insulin, despite slightly higher mean glucose. Finally, concerning hypoglycaemia, this study confirms findings from many other studies, which have consistently found a lower incidence of hypoglycaemia with Insulin glargine treatment than with NPH Insulin with otherwise similar regimens and at similar levels of glycaemic control [11–18]. In summary, we believe that the assertions made in these two letters are speculative and misguided. Our findings and conclusions are based on the largest and longest randomised trial comparing two types of Insulin. The study design was appropriate to address concerns about the effects that Insulin glargine might have on the progression of diabetic retinopathy, and the conclusions are well supported. We are confident that the reassuring findings and conclusions are correct as reported.
-
similar risk of malignancy with Insulin glargine and neutral protamine hagedorn NPH Insulin in patients with type 2 diabetes findings from a 5 year randomised open label study
Diabetologia, 2009Co-Authors: Julio Rosenstock, Vivian Fonseca, Janet B Mcgill, Matthew C Riddle, J P Halle, Irene Hramiak, P Johnston, M DavisAbstract:To the Editor: We have reported a randomised, long-term safety study comparing the effects of using the Insulin analogue glargine (A21Gly,B31Arg,B32Arg human Insulin) versus human neutral protamine Hagedorn (NPH) Insulin for 5 years in the management of type 2 diabetes [1]. The study, in which 1017 patients were randomised and treated, was designed to assess ocular complications of diabetes: there was no excess of such effects with Insulin glargine compared with NPH Insulin treatment and there was a similar slow progression of diabetic retinopathy with both types of Insulin. Because of recent concerns about postulated neoplastic effects of Insulins [2–5], we report here additional information from our study that bears on this question. In total, the mean cumulative exposure in our study was more than 4 years (1,524 days in the Insulin glargine group and 1,522 days in the NPH Insulin group), with more than 70% of patients exposed to more than 4 years of treatment (76% and 71%, respectively) (Table 1). Table 1 Summary of extent of exposure (safety population) The baseline demographics and diabetes status were similar between the two treatment groups (Insulin glargine vs NPH Insulin): diabetes duration (10.7 vs 10.8 years), BMI (34.5 vs 34.1 kg/m2), oral hypoglycaemic agent duration (9.0 vs 8.9 years), prior Insulin use (67% vs 70%), HbA1c (8.4% vs 8.3%) and fasting plasma glucose (10.5 vs 10.0 mmol/l). Although the study was not designed to investigate the frequency of tumour development, the long duration of the trial enables a comparative assessment of the occurrence of benign or malignant tumours with Insulin glargine and NPH Insulin during more than 4 years of exposure, captured as adverse events in the course of routine safety monitoring. The number of patients with treatment-emergent adverse events (defined as events that first occurred or worsened after randomisation) of neoplasm, summarised by System Organ Class and High-level Group Term levels using the standard Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary (version 10.0; Maintenance and Support Services Organization, Chantilly, VA, USA) [6], are shown in Table 2. Benign and malignant tumours reported by the investigators, along with those of unspecified pathology, are included. A more detailed listing of MedDRA-coded neoplasms is available [7]. Table 2 Patients with neoplasms reported as treatment-emergent adverse events The overall number of patients with neoplasms (using the standard MedDRA coding dictionary) occurring during the trial was similar in the two treatment groups: 57 patients (11.1%) in the Insulin glargine group vs 62 patients (12.3%) in the NPH Insulin group, with an RR for Insulin glargine of 0.90 (95% CI 0.64–1.26). In addition, when only the number of patients with malignant neoplasms reported as serious treatment-emergent events was captured, the rate was also similar in both treatment groups: 20 patients (3.9%) with 23 events in the Insulin glargine group vs 31 patients (6.2%) with 32 events in the NPH Insulin group, with an RR for Insulin glargine of 0.63 (95% CI 0.36–1.09). The number of patients with malignant breast tumours reported was also similar between the two treatment groups: three patients in the Insulin glargine group (all reported as serious) compared with five patients (four reported as serious) in the NPH Insulin group. The RR estimate of all malignant breast tumour cases, including non-serious cases (three in the Insulin glargine group vs five in the NPH Insulin group) numerically favours Insulin glargine (RR 0.59, 95% CI 0.14–2.44). Although the 95% CI includes 2, it must be noted that due to the small numbers of patients and the small number of cases, there was only a 22% power to reject a doubling in the risk (RR 2.0) of developing this tumour, should the true risks be equal. Considering all neoplasms (RR 0.9) and all malignant neoplasms (RR 0.63), the results numerically favour Insulin glargine with 95% upper CI limits of 1.26 and 1.09, respectively, indicating at most a 26% and 9% increase in risk. In summary, this study is the longest controlled treatment comparison of Insulin glargine versus NPH Insulin in patients with type 2 diabetes mellitus. No new safety issues emerged for either Insulin studied based on the data from this 5 year trial. Additional data reported here also confirm that there was no evidence of any difference in the rate of benign or malignant tumour development with Insulin glargine compared with NPH Insulin.
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similar progression of diabetic retinopathy with Insulin glargine and neutral protamine hagedorn NPH Insulin in patients with type 2 diabetes a long term randomised open label study
Diabetologia, 2009Co-Authors: Julio Rosenstock, Vivian Fonseca, Janet B Mcgill, Matthew C Riddle, J P Halle, Irene Hramiak, P Johnston, M DavisAbstract:Aims/hypothesis 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. Methods 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 HbA1c 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 patientlevel severity scale after treatment with either basal Insulin. Masked, centralised grading of seven-field stereoscopic fundus photographs was used.
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reduced hypoglycemia risk with Insulin glargine a meta analysis comparing Insulin glargine with human NPH Insulin in type 2 diabetes
Diabetes Care, 2005Co-Authors: Julio Rosenstock, George Dailey, Massimo Massibenedetti, Andreas Fritsche, Zhengning Lin, Alan SalzmanAbstract:OBJECTIVE —Insulin glargine (LANTUS) is a once-daily basal Insulin analog with a smooth 24-h time-action profile that provides effective glycemic control with reduced hypoglycemia risk (particularly nocturnal) compared with NPH Insulin in patients with type 2 diabetes. A recent “treat-to-target” study has shown that more patients on Insulin glargine reached HbA 1c levels ≤7.0% without confirmed nocturnal hypoglycemia compared with NPH Insulin. We further assessed the risk for hypoglycemia in a meta-analysis of controlled trials of a similar design for Insulin glargine versus once- or twice-daily NPH Insulin in adults with type 2 diabetes. RESEARCH DESIGN AND METHODS —All studies were 24–28 weeks long, except one 52-week study, for which interim 20-week data were used. RESULTS —Patient demographics were similar between the Insulin glargine ( n = 1,142) and NPH Insulin ( n = 1,162) groups. The proportion of patients achieving target HbA 1c (≤7.0%) was similar between Insulin glargine–and NPH Insulin–treated patients (30.8 and 32.1%, respectively). There was a consistent significant reduction of hypoglycemia risk associated with Insulin glargine, compared with NPH Insulin, in terms of overall symptomatic (11%; P = 0.0006) and nocturnal (26%; P P = 0.0442) and 59% ( P = 0.0231), respectively. CONCLUSIONS —These results confirmed that Insulin glargine given once daily reduces the risk of hypoglycemia compared with NPH Insulin, which can facilitate more aggressive Insulin treatment to a HbA 1c target of ≤7.0% in patients with type 2 diabetes.
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the treat to target trial randomized addition of glargine or human NPH Insulin to oral therapy of type 2 diabetic patients
Diabetes Care, 2003Co-Authors: Matthew C Riddle, Julio Rosenstock, John E GerichAbstract:OBJECTIVE —To compare the abilities and associated hypoglycemia risks of Insulin glargine and human NPH Insulin added to oral therapy of type 2 diabetes to achieve 7% HbA 1c . RESEARCH DESIGN AND METHODS —In a randomized, open-label, parallel, 24-week multicenter trial, 756 overweight men and women with inadequate glycemic control (HbA 1c >7.5%) on one or two oral agents continued prestudy oral agents and received bedtime glargine or NPH once daily, titrated using a simple algorithm seeking a target fasting plasma glucose (FPG) ≤100 mg/dl (5.5 mmol/l). Outcome measures were FPG, HbA 1c , hypoglycemia, and percentage of patients reaching HbA 1c ≤7% without documented nocturnal hypoglycemia. RESULTS —Mean FPG at end point was similar with glargine and NPH (117 vs. 120 mg/dl [6.5 vs. 6.7 mmol/l]), as was HbA 1c (6.96 vs. 6.97%). A majority of patients (∼60%) attained HbA 1c ≤7% with each Insulin type. However, nearly 25% more patients attained this without documented nocturnal hypoglycemia (≤72 mg/dl [4.0 mmol/l]) with glargine (33.2 vs. 26.7%, P CONCLUSIONS —Systematically titrating bedtime basal Insulin added to oral therapy can safely achieve 7% HbA 1c in a majority of overweight patients with type 2 diabetes with HbA 1c between 7.5 and 10.0% on oral agents alone. In doing this, glargine causes significantly less nocturnal hypoglycemia than NPH, thus reducing a leading barrier to initiating Insulin. This simple regimen may facilitate earlier and effective Insulin use in routine medical practice, improving achievement of recommended standards of diabetes care.
M A Gall - One of the best experts on this subject based on the ideXlab platform.
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Insulin detemir compared with NPH Insulin in children and adolescents with type 1 diabetes
Diabetic Medicine, 2007Co-Authors: Kenneth Robertson, E Schoenle, Zoran Gucev, L Mordhorst, M A Gall, Johnny LudvigssonAbstract:Aims This study compared the effect of Insulin detemir on glycaemic control (HbA1c, fasting plasma glucose and variability thereof) with that of Neutral Protamine Hagedorn human isophane (NPH) Insulin, both combined with Insulin aspart, in children with Type 1 diabetes mellitus, and compared the safety of these treatments. Methods In this 26-week, open-label, randomized (2 : 1), parallel-group study, 347 (140 prepubertal and 207 pubertal) children with Type 1 diabetes, aged 6–17 years, received Insulin detemir (n = 232) or NPH Insulin (n = 115) once or twice daily, according to the prestudy regimen, plus premeal Insulin aspart. Results The mean HbA1c decreased by ∼0.8% with both treatments. After 26 weeks, the mean difference in HbA1c was 0.1% (95% confidence interval −0.1, 0.3) (Insulin detemir 8.0%, NPH Insulin 7.9%). Within-subject variation in self-measured fasting plasma glucose was significantly lower with Insulin detemir than with NPH Insulin (SD 3.3 vs. 4.3, P < 0.001), as was mean fasting plasma glucose (8.4 vs. 9.6 mmol/l, P = 0.022). The risk of nocturnal hypoglycaemia (22.00–07.00 h) was 26% lower with Insulin detemir (P = 0.041) and the risk of 24-h hypoglycaemia was similar with the two treatments (P = 0.351). The mean body mass index (BMI) Z-score was lower with Insulin detemir (P < 0.001). Conclusions Basal-bolus treatment with Insulin detemir or NPH Insulin and premeal Insulin aspart in children and adolescents with Type 1 diabetes mellitus improved HbA1c to a similar degree. The lower and more predictable fasting plasma glucose, lower risk of nocturnal hypoglycaemia and lower BMI observed with Insulin detemir are clinically significant advantages compared with NPH Insulin.
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Insulin detemir lowers the risk of hypoglycaemia and provides more consistent plasma glucose levels compared with NPH Insulin in type 1 diabetes
Diabetic Medicine, 2006Co-Authors: K Kolendorf, M A Gall, Johan Jendle, G P Ross, I Pavlicrenar, G Perriello, A Philotheou, Simon HellerAbstract:Aims Hypoglycaemia remains a major barrier preventing optimal glycaemic control in Type 1 diabetes due to the limitations of conventional Insulin preparations. We investigated whether basal-bolus therapy with Insulin detemir (detemir), a new soluble basal Insulin analogue, was more effective in reducing the risk of hypoglycaemia compared with NPH Insulin (NPH). Methods In this multinational, open-label, cross-over trial, 130 individuals with Type 1 diabetes received detemir and NPH twice daily in a randomized order in combination with premeal Insulin aspart (IAsp) during two 16-week treatment periods. Risk of hypoglycaemia was based on self-measured plasma glucose (SMPG) and self-reported episodes during the last 10 weeks of each period. Results Risk of nocturnal and overall hypoglycaemia was, respectively, 50% and 18% lower with detemir than with NPH (P < 0.001). A total of 19 severe hypoglycaemic episodes occurred during treatment with detemir compared with 33 with NPH (NS). HbA1c decreased by 0.3% point with both treatments and was comparable at 7.6% (± sem 0.06%, 95% confidence interval −0.106, 0.108) after 16 weeks with similar doses of basal Insulin. Within-person variation in mean plasma glucose was lower with detemir than with NPH (sd 3.00 vs. 3.33, P < 0.001), as was prebreakfast SMPG (P < 0.0001). Conclusions Detemir was associated with a significantly lower risk of hypoglycaemia compared with NPH at similar HbA1c when used in combination with mealtime IAsp. The more consistent plasma glucose levels observed with detemir may allow people to aim for tighter glycaemic control without an increased risk of hypoglycaemia.
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Insulin analogues Insulin detemir and Insulin aspart versus traditional human Insulins NPH Insulin and regular human Insulin in basal bolus therapy for patients with type 1 diabetes
Diabetologia, 2004Co-Authors: Kjeld Hermansen, P Fontaine, Karmen Kukolja, V Peterkova, G Leth, M A GallAbstract:The aim of the trial was to compare the efficacy and tolerability of two types of basal-bolus therapy, using either the soluble long-acting basal Insulin analogue, Insulin detemir, in combination with the rapid-acting analogue, Insulin aspart, or NPH Insulin in combination with mealtime regular human Insulin. In this 18-week, 1:1 randomised, open-labelled, parallel trial, 595 patients with Type 1 diabetes mellitus received Insulin detemir or NPH Insulin in the morning and at bedtime in combination with mealtime Insulin aspart or regular human Insulin respectively. Glycaemic control with Insulin detemir/Insulin aspart was improved in comparison with NPH Insulin/regular human Insulin (HbA1c: 7.88% vs 8.11%; mean difference: −0.22% point [95% CI: −0.34 to −0.10]; p<0.001). Self-measured 8-point plasma glucose profiles differed between the groups (p<0.001), with lower postprandial plasma glucose levels in the Insulin detemir/Insulin aspart group. Within-person day-to-day variation in plasma glucose was lower with Insulin detemir/Insulin aspart than with NPH Insulin/regular human Insulin (SD: 2.88 vs 3.12 mmol/l; p<0.001). Risk of overall and nocturnal hypoglycaemia (23.00–06.00 hours) was, respectively, 21% (p=0.036) and 55% (p<0.001) lower in the Insulin detemir/Insulin aspart group than in the NPH Insulin/regular human Insulin group. Body weight (adjusted for baseline and change in HbA1c) was 1 kg lower with Insulin detemir/Insulin aspart than with NPH Insulin/regular human Insulin (p<0.001). Basal-bolus therapy using Insulin detemir/Insulin aspart offers a better balance of control and tolerability than with NPH Insulin/regular human Insulin. The low variability and more physiological action profiles generated with these Insulin analogues resulted in improved glycaemic control with lower risk of hypoglycaemia and no concomitant body weight increase.
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Insulin analogues Insulin detemir and Insulin aspart versus traditional human Insulins NPH Insulin and regular human Insulin in basal bolus therapy for patients with type 1 diabetes
Diabetologia, 2004Co-Authors: Kjeld Hermansen, P Fontaine, Karmen Kukolja, V Peterkova, G Leth, M A GallAbstract:Aims/hypothesis The aim of the trial was to compare the efficacy and tolerability of two types of basal-bolus therapy, using either the soluble long-acting basal Insulin analogue, Insulin detemir, in combination with the rapid-acting analogue, Insulin aspart, or NPH Insulin in combination with mealtime regular human Insulin.
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Insulin detemir is characterized by a consistent pharmacokinetic profile across age groups in children adolescents and adults with type 1 diabetes
Diabetes Care, 2003Co-Authors: Thomas Danne, Kerstin Lupke, Kerstin Walte, Wolfgang Von Schuetz, M A GallAbstract:OBJECTIVE —This trial aimed to characterize for the first time the pharmacokinetic profile of Insulin detemir, the novel soluble basal Insulin analog, in children and adolescents compared with adults. Comparisons were also made with NPH Insulin to determine any between-treatment difference in the effect of age on pharmacokinetic profile. RESEARCH DESIGN AND METHODS —This single-center, open-label, randomized, crossover trial included children (aged 6–12 years, n = 13), adolescents (aged 13–17 years, n = 10), and adults (aged 18–65 years, n = 11) of both sexes. Subjects were given single doses of 0.5 units/kg s.c. Insulin detemir or 0.5 IU/kg NPH Insulin on 2 separate days. Serial blood sampling was performed for 24 h for analysis of serum Insulin detemir, human Insulin, and glucose concentrations. RESULTS —The mean pharmacokinetic profile of Insulin detemir was similar across all three age-groups. This was determined by statistical analyses of the data, which showed no overall age effect or between-group differences when pairwise comparisons were made between children (or adolescents) and adults on the parameters of the area under the curve (AUC), AUC from zero to infinity, AUC from 0 to 24 h [AUC (0–24 h) ], and the maximum concentration measured during the 24 h after closing. No overall age effect for AUC (0–24 h) and C max was detected for NPH Insulin, but data were only analyzable from seven adults and pairwise comparisons did indicate that children and adults had different pharmacokinetic profiles. Less total variability in the pharmacokinetics of Insulin detemir than NPH Insulin was indicated by lower coefficients of variation in AUC, C max , and time to maximum concentration in all three age-groups. CONCLUSIONS —The data suggest that Insulin detemir can be used in children and adolescents with type 1 diabetes using titration guidelines similar to those used in adults. Moreover, Insulin detemir may offer the advantage of greater predictability of response in comparison to NPH Insulin due to lower total variability and a lesser degree of kinetic disparity across age-groups.
Randy J Seeley - One of the best experts on this subject based on the ideXlab platform.
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Insulin detemir is transported from blood to cerebrospinal fluid and has prolonged central anorectic action relative to NPH Insulin
Diabetes, 2015Co-Authors: Denovan P Begg, Aaron A May, Joram D Mul, Min Liu, David A Dalessio, Randy J SeeleyAbstract:Insulin detemir (DET) reduces glycemia comparably to other long-acting Insulin formulations but causes less weight gain. Insulin signaling in the brain is catabolic, reducing food intake. We hypothesized that DET reduces weight gain, relative to other Insulins, owing to increased transport into the central nervous system and/or increased catabolic action within the brain. Transport of DET and NPH Insulin into the cerebrospinal fluid (CSF) was compared over several hours and after the administration of different doses peripherally in rats. DET and NPH had comparable saturable, receptor-mediated transport into the CSF. CSF Insulin remained elevated significantly longer after intraperitoneal DET than after NPH. When administered acutely into the 3rd cerebral ventricle, both DET and NPH Insulin reduced food intake and body weight at 24 h, and both food intake and body weight remained lower after DET than after NPH after 48 h. In direct comparison with another long-acting Insulin, Insulin glargine (GLAR), DET led to more prolonged increases in CSF Insulin despite a shorter plasma half-life in both rats and mice. Additionally, peripheral DET administration reduced weight gain and increased CSF Insulin compared with saline or GLAR in mice. Overall, these data support the hypothesis that DET has distinct effects on energy balance through enhanced and prolonged centrally mediated reduction of food intake.
E Draeger - One of the best experts on this subject based on the ideXlab platform.
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comparison of three multiple injection regimens for type 1 diabetes morning plus dinner or bedtime administration of Insulin detemir vs morning plus bedtime NPH Insulin
Diabetic Medicine, 2005Co-Authors: Thomas R Pieber, E Draeger, A Kristensen, V GrillAbstract:Aims This trial investigated the efficacy and safety of two different administration-time regimens with Insulin detemir (IDet) to that of a conventional basal Insulin regimen with NPH Insulin (NPH). Methods This multinational, 16-week, open, parallel group trial included 400 people with Type 1 diabetes mellitus (DM) randomized to IDet either morning and before dinner (IDetmorn+din) or morning and bedtime (IDetmorn+bed), or to NPH morning and bedtime (NPHmorn+bed), all in combination with mealtime Insulin aspart (IAsp). Results HbA1c was comparable between the three groups after 16 weeks (P = 0.64), with reductions of 0.39–0.49% points. Lower fasting plasma glucose (FPG) was observed with IDetmorn+din and IDetmorn+bed compared with NPHmorn+bed (9.8 and 9.1 vs. 11.1 mmol/l, P = 0.006), whereas the IDet groups did not differ (P = 0.15). Within-person variation in self-measured FPG was significantly lower for both IDet regimens (sd IDetmorn+din 2.5, IDetmorn+bed 2.6 mmol/l) than for NPHmorn+bed (sd 3.1 mmol/l, P < 0.001), but was comparable between the IDet groups (P = 0.48). Ten-point plasma glucose profiles were lower between dinner and breakfast in the IDetmorn+din group (P = 0.043), compared with the two other groups. Risk of overall and nocturnal hypoglycaemia was similar for the three groups. Lower mean bodyweight was observed with IDet compared with NPH after 16 weeks (difference: IDetmorn+din−1.3 kg, P < 0.001, IDetmorn+bed−0.6 kg, P = 0.050). Conclusions Both IDet regimens were well tolerated and provided lower and less variable glucose levels with no, or less, weight gain than NPH at comparable HbA1c. IDet can be administered either at dinner or bedtime, with similar glycaemic control according to the need of the individual person. Pieber T R, Grill V, Kristensen A, Draeger E: Treatment with Insulin detemir allows flexible timing of administration in subjects with Type 1 diabetes. Diabetes 2003; 52 (Suppl. 1): A130.
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lower within subject variability of fasting blood glucose and reduced weight gain with Insulin detemir compared to NPH Insulin in patients with type 2 diabetes
Diabetes Obesity and Metabolism, 2005Co-Authors: T Haak, A Tiengo, E Draeger, M Suntum, W WaldhauslAbstract:Aim: The aim of this study was to compare the efficacy and safety of a basal-bolus Insulin regimen comprising either Insulin detemir or neural protamine hagedorn (NPH) Insulin in combination with mealtime Insulin aspart in patients with type 2 diabetes. Methods: This was a 26-week, multinational, open-label, parallel group trial with 505 patients with type 2 diabetes (mean age, 60.4 ± 8.6 years; mean BMI, 30.4 ± 5.3 kg/m2; mean HbA1c, 7.9 ± 1.3%). Patients, randomized 2 : 1 to Insulin detemir or NPH Insulin, received basal Insulin either once or twice daily according to their pretrial Insulin treatment and Insulin aspart at mealtimes. Results: After 26 weeks of treatment, significant reductions in HbA1c were observed for Insulin detemir (0.2%-points, p = 0.004) and NPH Insulin (0.4%-points; p = 0.0001); HbA1c levels were comparable at study end (Insulin detemir, 7.6%; NPH Insulin, 7.5%). The number of basal Insulin injections administered per day had no effect on HbA1c levels (p = 0.50). Nine-point self-measured blood glucose (SMBG) profiles were similar for the two treatment groups (p = 0.58), as were reductions in fasting plasma glucose (FPG) (Insulin detemir, 0.5 mmol/l; NPH Insulin, 0.6 mmol/l). At study end, FPG concentrations were similar for the two treatment groups (p = 0.66). By contrast, within-subject day-to-day variation in fasting SMBG was significantly lower with Insulin detemir (p = 0.021). Moreover, patients receiving Insulin detemir gained significantly less body weight than those who were administered NPH Insulin (1.0 and 1.8 kg, respectively, p = 0.017). The frequency of adverse events and the risk of hypoglycaemia were comparable for the two treatment groups. Conclusions: Patients with type 2 diabetes, treated for 26 weeks with Insulin detemir plus Insulin aspart at mealtimes, experienced comparable glycaemic control but significantly lower within-subject variability and less weight gain compared to patients treated with NPH Insulin and Insulin aspart. Insulin detemir was well tolerated and had a similar safety profile to NPH Insulin.
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Insulin detemir used in basal bolus therapy in people with type 1 diabetes is associated with a lower risk of nocturnal hypoglycaemia and less weight gain over 12 months in comparison to NPH Insulin
Diabetes Obesity and Metabolism, 2005Co-Authors: I De Leeuw, E Draeger, P Vague, J L Selam, Svein Skeie, H Lang, Jan W F ElteAbstract:Aim: The aim of this study was to compare the long-term safety and efficacy of twice-daily Insulin detemir or NPH Insulin as the basal component of basal-bolus therapy in people with type 1 diabetes. Methods: A multicentre, open-label, parallel-group study was conducted over 12 months and completed by 308 people (from an original randomized cohort of 428). Patients were randomized in a 2 : 1 ratio to receive Insulin detemir or NPH Insulin before breakfast and dinner, with Insulin aspart at mealtimes. Results: Glycaemic control improved in both groups with HbA1c decreasing by 0.64 and 0.56% point in the Insulin detemir and NPH Insulin groups, reaching baseline-adjusted final values of 7.53 ± 0.10% and 7.59 ± 0.13%, respectively. No significant difference was apparent between treatments in terms of HbA1c, fasting plasma glucose or 9-point blood glucose profiles. Fewer hypoglycaemic events (major and minor) occurred in association with Insulin detemir compared with NPH Insulin, but the overall hypoglycaemic risk did not differ statistically significantly (RR for detemir, 0.78 [0.56–1.08]). However, the risk of nocturnal hypoglycaemia during the maintenance phase (month 2–12) was 32% lower in the detemir group (p = 0.02) and lower in every month. This risk reduction remained statistically significant after correction for HbA1c. After 12 months, baseline-adjusted mean body weight was significantly lower in the Insulin detemir group than in the NPH Insulin group (p < 0.001). Conclusions: In long-term basal-bolus therapy, Insulin detemir with Insulin aspart as mealtime Insulin is well tolerated and reduces the risks of nocturnal hypoglycaemia and weight gain compared to NPH Insulin.
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lower within subject variability of Insulin detemir in comparison to NPH Insulin and Insulin glargine in people with type 1 diabetes
Diabetes, 2004Co-Authors: Tim Heise, B Ronn, Leszek Nosek, Lars Endahl, Lutz Heinemann, Christoph Kapitza, E DraegerAbstract:The aim of this randomized double-blind study was to compare the within-subject variability of the glucose-lowering effect of a novel Insulin analog, Insulin detemir, with that of Insulin glargine and NPH Insulin in people with type 1 diabetes. Fifty-four subjects (32 males and 22 females, age 38 +/- 10 years [mean +/- SD], BMI 24 +/- 2 kg/m(2), HbA(1c) 7.5 +/- 1.2%, diabetes duration 18 +/- 9 years) participated in this parallel group comparison. Each subject received four single subcutaneous doses of 0.4 units/kg of either Insulin detemir (n = 18), Insulin glargine (n = 16), or human NPH Insulin (n = 17) under euglycemic glucose clamp conditions (target blood glucose concentration 5.5 mmol/l) on four identical study days. The pharmacodynamic (glucose infusion rates [GIRs]) and pharmacokinetic (serum concentrations of Insulin detemir, human Insulin, and Insulin glargine) properties of the basal Insulin preparations were recorded for 24 h postdosing. Insulin detemir was associated with significantly less within-subject variability than both NPH Insulin and Insulin glargine, as assessed by the coefficient of variation (CV) for the pharmacodynamic end points studied [GIR-AUC((0-12 h)) 27% (detemir) vs. 59% (NPH) vs. 46% (glargine); GIR-AUC((0-24 h)) 27 vs. 68 vs. 48%; GIR(max) 23 vs. 46 vs. 36%; P < 0.001 for all comparisons]. Insulin detemir also provided less within-subject variability in the pharmacokinetic end points: maximal concentration (C(max)) 18 vs. 24 vs. 34%; INS-AUC((0- infinity )) 14 vs. 28 vs. 33%. The results suggest that Insulin detemir has a significantly more predictable glucose-lowering effect than both NPH Insulin and Insulin glargine.
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Insulin detemir is associated with more predictable glycemic control and reduced risk of hypoglycemia than NPH Insulin in patients with type 1 diabetes on a basal bolus regimen with premeal Insulin aspart
Diabetes Care, 2003Co-Authors: P Vague, Allan Kristensen, J L Selam, Svein Skeie, Ivo H De Leeuw, Jan W F Elte, Hanne Haahr, E DraegerAbstract:OBJECTIVE —Insulin detemir is a soluble basal Insulin analog with a unique mechanism of protracted action designed to reduce the variability associated with conventional basal Insulins. This trial compared the glycemic control, risk of hypoglycemia, and effect on body weight of Insulin detemir and NPH Insulin in patients with type 1 diabetes treated with rapid-acting Insulin aspart at meals. RESEARCH DESIGN AND METHODS —This study was a 6-month multinational open parallel-group comparison conducted at 46 centers in five countries and included 448 patients with type 1 diabetes randomized 2:1 to Insulin detemir or NPH Insulin, respectively. RESULTS —After 6 months, comparable HbA 1c levels were found between the two treatment groups. Fasting plasma glucose tended to be lower in patients treated with Insulin detemir, but this difference was not statistically significant (−0.76 mmol/l, P = 0.097). Within-subject variation in self-measured fasting blood glucose was lower with Insulin detemir than with NPH Insulin (SD 3.37 vs. 3.78 mmol/l, P P P P = 0.05). Body weight was significantly lower with Insulin detemir at the end of the trial ( P CONCLUSIONS —Treatment with Insulin detemir resulted in more predictable glycemic control, with smoother plasma glucose profiles than NPH Insulin and a significant reduction in the risk of hypoglycemia. The reduction in body weight with Insulin detemir is a potential additional advantage. Regimens optimized for Insulin detemir may be able to improve glycemic control beyond that possible with NPH Insulin.
