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Karl Horvath - One of the best experts on this subject based on the ideXlab platform.
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(Ultra-)long-acting Insulin analogues versus NPH Insulin (human Isophane Insulin) for adults with type 2 diabetes mellitus.
The Cochrane database of systematic reviews, 2020Co-Authors: Thomas Semlitsch, Jennifer Engler, Andrea Siebenhofer, Klaus Jeitler, Andrea Berghold, Karl HorvathAbstract:Evidence that antihyperglycaemic therapy is beneficial for people with type 2 diabetes mellitus is conflicting. While the United Kingdom Prospective Diabetes Study (UKPDS) found tighter glycaemic control to be positive, other studies, such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, found the effects of an intensive therapy to lower blood glucose to near normal levels to be more harmful than beneficial. Study results also showed different effects for different antihyperglycaemic drugs, regardless of the achieved blood glucose levels. In consequence, firm conclusions on the effect of interventions on patient-relevant outcomes cannot be drawn from the effect of these interventions on blood glucose concentration alone. In theory, the use of newer Insulin analogues may result in fewer macrovascular and microvascular events. To compare the effects of long-term treatment with (ultra-)long-acting Insulin analogues (Insulin glargine U100 and U300, Insulin detemir and Insulin degludec) with NPH (neutral protamine Hagedorn) Insulin (human Isophane Insulin) in adults with type 2 diabetes mellitus. For this Cochrane Review update, we searched CENTRAL, MEDLINE, Embase, ICTRP Search Portal and ClinicalTrials.gov. The date of the last search was 5 November 2019, except Embase which was last searched 26 January 2017. We applied no language restrictions. We included randomised controlled trials (RCTs) comparing the effects of treatment with (ultra-)long-acting Insulin analogues to NPH in adults with type 2 diabetes mellitus. Two review authors independently selected trials, assessed risk of bias, extracted data and evaluated the overall certainty of the evidence using GRADE. Trials were pooled using random-effects meta-analyses. We identified 24 RCTs. Of these, 16 trials compared Insulin glargine to NPH Insulin and eight trials compared Insulin detemir to NPH Insulin. In these trials, 3419 people with type 2 diabetes mellitus were randomised to Insulin glargine and 1321 people to Insulin detemir. The duration of the included trials ranged from 24 weeks to five years. For studies, comparing Insulin glargine to NPH Insulin, target values ranged from 4.0 mmol/L to 7.8 mmol/L (72 mg/dL to 140 mg/dL) for fasting blood glucose (FBG), from 4.4 mmol/L to 6.6 mmol/L (80 mg/dL to 120 mg/dL) for nocturnal blood glucose and less than 10 mmol/L (180 mg/dL) for postprandial blood glucose, when applicable. Blood glucose and glycosylated haemoglobin A1c (HbA1c) target values for studies comparing Insulin detemir to NPH Insulin ranged from 4.0 mmol/L to 7.0 mmol/L (72 mg/dL to 126 mg/dL) for FBG, less than 6.7 mmol/L (120 mg/dL) to less than 10 mmol/L (180 mg/dL) for postprandial blood glucose, 4.0 mmol/L to 7.0 mmol/L (72 mg/dL to 126 mg/dL) for nocturnal blood glucose and 5.8% to less than 6.4% HbA1c, when applicable. All trials had an unclear or high risk of bias for several risk of bias domains. Overall, Insulin glargine and Insulin detemir resulted in fewer participants experiencing hypoglycaemia when compared with NPH Insulin. Changes in HbA1c were comparable for long-acting Insulin analogues and NPH Insulin. Insulin glargine compared to NPH Insulin had a risk ratio (RR) for severe hypoglycaemia of 0.68 (95% confidence interval (CI) 0.46 to 1.01; P = 0.06; absolute risk reduction (ARR) -1.2%, 95% CI -2.0 to 0; 14 trials, 6164 participants; very low-certainty evidence). The RR for serious hypoglycaemia was 0.75 (95% CI 0.52 to 1.09; P = 0.13; ARR -0.7%, 95% CI -1.3 to 0.2; 10 trials, 4685 participants; low-certainty evidence). Treatment with Insulin glargine reduced the incidence of confirmed hypoglycaemia and confirmed nocturnal hypoglycaemia. Treatment with Insulin detemir compared to NPH Insulin found an RR for severe hypoglycaemia of 0.45 (95% CI 0.17 to 1.20; P = 0.11; ARR -0.9%, 95% CI -1.4 to 0.4; 5 trials, 1804 participants; very low-certainty evidence). The Peto odds ratio for serious hypoglycaemia was 0.16, 95% CI 0.04 to 0.61; P = 0.007; ARR -0.9%, 95% CI -1.1 to -0.4; 5 trials, 1777 participants; low-certainty evidence). Treatment with detemir also reduced the incidence of confirmed hypoglycaemia and confirmed nocturnal hypoglycaemia. Information on patient-relevant outcomes such as death from any cause, diabetes-related complications, health-related quality of life and socioeconomic effects was insufficient or lacking in almost all included trials. For those outcomes for which some data were available, there were no meaningful differences between treatment with glargine or detemir and treatment with NPH. There was no clear difference between Insulin-analogues and NPH Insulin in terms of weight gain. The incidence of adverse events was comparable for people treated with glargine or detemir, and people treated with NPH. We found no trials comparing ultra-long-acting Insulin glargine U300 or Insulin degludec with NPH Insulin. While the effects on HbA1c were comparable, treatment with Insulin glargine and Insulin detemir resulted in fewer participants experiencing hypoglycaemia when compared with NPH Insulin. Treatment with Insulin detemir also reduced the incidence of serious hypoglycaemia. However, serious hypoglycaemic events were rare and the absolute risk reducing effect was low. Approximately one in 100 people treated with Insulin detemir instead of NPH Insulin benefited. In the studies, low blood glucose and HbA1c targets, corresponding to near normal or even non-diabetic blood glucose levels, were set. Therefore, results from the studies are only applicable to people in whom such low blood glucose concentrations are targeted. However, current guidelines recommend less-intensive blood glucose lowering for most people with type 2 diabetes in daily practice (e.g. people with cardiovascular diseases, a long history of type 2 diabetes, who are susceptible to hypoglycaemia or older people). Additionally, low-certainty evidence and trial designs that did not conform with current clinical practice meant it remains unclear if the same effects will be observed in daily clinical practice. Most trials did not report patient-relevant outcomes. Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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ultra long acting Insulin analogues versus nph Insulin human Isophane Insulin for adults with type 2 diabetes mellitus
Cochrane Database of Systematic Reviews, 2020Co-Authors: Thomas Semlitsch, Jennifer Engler, Andrea Siebenhofer, Klaus Jeitler, Andrea Berghold, Karl HorvathAbstract:Background Evidence that antihyperglycaemic therapy is beneficial for people with type 2 diabetes mellitus is conflicting. While the United Kingdom Prospective Diabetes Study (UKPDS) found tighter glycaemic control to be positive, other studies, such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, found the effects of an intensive therapy to lower blood glucose to near normal levels to be more harmful than beneficial. Study results also showed different effects for different antihyperglycaemic drugs, regardless of the achieved blood glucose levels. In consequence, firm conclusions on the effect of interventions on patient-relevant outcomes cannot be drawn from the effect of these interventions on blood glucose concentration alone. In theory, the use of newer Insulin analogues may result in fewer macrovascular and microvascular events. Objectives To compare the effects of long-term treatment with (ultra-)long-acting Insulin analogues (Insulin glargine U100 and U300, Insulin detemir and Insulin degludec) with NPH (neutral protamine Hagedorn) Insulin (human Isophane Insulin) in adults with type 2 diabetes mellitus. Search methods For this Cochrane Review update, we searched CENTRAL, MEDLINE, Embase, ICTRP Search Portal and ClinicalTrials.gov. The date of the last search was 5 November 2019, except Embase which was last searched 26 January 2017. We applied no language restrictions. Selection criteria We included randomised controlled trials (RCTs) comparing the effects of treatment with (ultra-)long-acting Insulin analogues to NPH in adults with type 2 diabetes mellitus. Data collection and analysis Two review authors independently selected trials, assessed risk of bias, extracted data and evaluated the overall certainty of the evidence using GRADE. Trials were pooled using random-effects meta-analyses. Main results We identified 24 RCTs. Of these, 16 trials compared Insulin glargine to NPH Insulin and eight trials compared Insulin detemir to NPH Insulin. In these trials, 3419 people with type 2 diabetes mellitus were randomised to Insulin glargine and 1321 people to Insulin detemir. The duration of the included trials ranged from 24 weeks to five years. For studies, comparing Insulin glargine to NPH Insulin, target values ranged from 4.0 mmol/L to 7.8 mmol/L (72 mg/dL to 140 mg/dL) for fasting blood glucose (FBG), from 4.4 mmol/L to 6.6 mmol/L (80 mg/dL to 120 mg/dL) for nocturnal blood glucose and less than 10 mmol/L (180 mg/dL) for postprandial blood glucose, when applicable. Blood glucose and glycosylated haemoglobin A1c (HbA1c) target values for studies comparing Insulin detemir to NPH Insulin ranged from 4.0 mmol/L to 7.0 mmol/L (72 mg/dL to 126 mg/dL) for FBG, less than 6.7 mmol/L (120 mg/dL) to less than 10 mmol/L (180 mg/dL) for postprandial blood glucose, 4.0 mmol/L to 7.0 mmol/L (72 mg/dL to 126 mg/dL) for nocturnal blood glucose and 5.8% to less than 6.4% HbA1c, when applicable. All trials had an unclear or high risk of bias for several risk of bias domains. Overall, Insulin glargine and Insulin detemir resulted in fewer participants experiencing hypoglycaemia when compared with NPH Insulin. Changes in HbA1c were comparable for long-acting Insulin analogues and NPH Insulin. Insulin glargine compared to NPH Insulin had a risk ratio (RR) for severe hypoglycaemia of 0.68 (95% confidence interval (CI) 0.46 to 1.01; P = 0.06; absolute risk reduction (ARR) -1.2%, 95% CI -2.0 to 0; 14 trials, 6164 participants; very low-certainty evidence). The RR for serious hypoglycaemia was 0.75 (95% CI 0.52 to 1.09; P = 0.13; ARR -0.7%, 95% CI -1.3 to 0.2; 10 trials, 4685 participants; low-certainty evidence). Treatment with Insulin glargine reduced the incidence of confirmed hypoglycaemia and confirmed nocturnal hypoglycaemia. Treatment with Insulin detemir compared to NPH Insulin found an RR for severe hypoglycaemia of 0.45 (95% CI 0.17 to 1.20; P = 0.11; ARR -0.9%, 95% CI -1.4 to 0.4; 5 trials, 1804 participants; very low-certainty evidence). The Peto odds ratio for serious hypoglycaemia was 0.16, 95% CI 0.04 to 0.61; P = 0.007; ARR -0.9%, 95% CI -1.1 to -0.4; 5 trials, 1777 participants; low-certainty evidence). Treatment with detemir also reduced the incidence of confirmed hypoglycaemia and confirmed nocturnal hypoglycaemia. Information on patient-relevant outcomes such as death from any cause, diabetes-related complications, health-related quality of life and socioeconomic effects was insufficient or lacking in almost all included trials. For those outcomes for which some data were available, there were no meaningful differences between treatment with glargine or detemir and treatment with NPH. There was no clear difference between Insulin-analogues and NPH Insulin in terms of weight gain. The incidence of adverse events was comparable for people treated with glargine or detemir, and people treated with NPH. We found no trials comparing ultra-long-acting Insulin glargine U300 or Insulin degludec with NPH Insulin. Authors' conclusions While the effects on HbA1c were comparable, treatment with Insulin glargine and Insulin detemir resulted in fewer participants experiencing hypoglycaemia when compared with NPH Insulin. Treatment with Insulin detemir also reduced the incidence of serious hypoglycaemia. However, serious hypoglycaemic events were rare and the absolute risk reducing effect was low. Approximately one in 100 people treated with Insulin detemir instead of NPH Insulin benefited. In the studies, low blood glucose and HbA1c targets, corresponding to near normal or even non-diabetic blood glucose levels, were set. Therefore, results from the studies are only applicable to people in whom such low blood glucose concentrations are targeted. However, current guidelines recommend less-intensive blood glucose lowering for most people with type 2 diabetes in daily practice (e.g. people with cardiovascular diseases, a long history of type 2 diabetes, who are susceptible to hypoglycaemia or older people). Additionally, low-certainty evidence and trial designs that did not conform with current clinical practice meant it remains unclear if the same effects will be observed in daily clinical practice. Most trials did not report patient-relevant outcomes.
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long acting Insulin analogues versus nph Insulin human Isophane Insulin for type 2 diabetes mellitus
Cochrane Database of Systematic Reviews, 2007Co-Authors: Karl Horvath, Klaus Jeitler, Andrea Berghold, Susanne H Ebrahim, Thomas W Gratzer, Johannes Plank, Thomas Kaiser, Thomas R Pieber, Andrea SiebenhoferAbstract:Background Despite indications from epidemiological trials that higher blood glucose concentrations are associated with a higher risk for developing micro- and macrovascular complications, evidence for a beneficial effect of antihyperglycaemic therapy in patients with type 2 diabetes mellitus is conflicting. Two large studies, the United Kingdom Prospective Diabetes Study (UKPDS) and the University Group Diabetes Program (UGDP), did not find a reduction of cardiovascular endpoints through improvement of metabolic control. The theoretical benefits of newer Insulin analogues might result in fewer macrovascular and microvascular events. Objectives To assess the effects of long-term treatment with long-acting Insulin analogues (Insulin glargine and Insulin detemir) compared to NPH Insulin in patients with type 2 diabetes mellitus. Search methods Studies were obtained from computerised searches of MEDLINE, EMBASE, The Cochrane Library and communication with experts in the field as well as Insulin producing companies. Selection criteria Studies were included if they were randomised controlled trials in adults with diabetes mellitus type 2 and had a trial duration of at least 24 weeks. Data collection and analysis Two authors independently assessed trial quality and extracted data. Pooling of studies by means of random-effects meta-analyses was performed. Main results Six studies comparing Insulin glargine to NPH (Neutral Protamine Hagedorn) Insulin and two studies comparing Insulin detemir to NPH Insulin were identified. In these trials, 1715 patients were randomised to Insulin glargine and 578 patients to Insulin detemir. Duration of the included trials ranged from 24 to 52 weeks. Metabolic control, measured by glycosylated haemoglobin A1c (HbA1c) as a surrogate endpoint, and adverse effects did not differ in a clinical relevant way between treatment groups. While no statistically significant difference for severe hypoglycaemia rates was shown in any of the trials, the rate of symptomatic, overall and nocturnal hypoglycaemia was statistically significantly lower in patients treated with either Insulin glargine or detemir. No evidence for a beneficial effect of long-acting analogues on patient-oriented outcomes like mortality, morbidity, quality of life or costs could be obtained. Authors' conclusions Our analysis suggests, if at all only a minor clinical benefit of treatment with long-acting Insulin analogues for patients with diabetes mellitus type 2 treated with "basal" Insulin regarding symptomatic nocturnal hypoglycaemic events. Until long-term efficacy and safety data are available, we suggest a cautious approach to therapy with Insulin glargine or detemir.
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The Cochrane Library - Long acting Insulin analogues versus NPH Insulin (human Isophane Insulin) for type 2 diabetes mellitus
The Cochrane database of systematic reviews, 2007Co-Authors: Karl Horvath, Klaus Jeitler, Andrea Berghold, Susanne H Ebrahim, Thomas W Gratzer, Johannes Plank, Thomas Kaiser, Thomas R Pieber, Andrea SiebenhoferAbstract:Background Despite indications from epidemiological trials that higher blood glucose concentrations are associated with a higher risk for developing micro- and macrovascular complications, evidence for a beneficial effect of antihyperglycaemic therapy in patients with type 2 diabetes mellitus is conflicting. Two large studies, the United Kingdom Prospective Diabetes Study (UKPDS) and the University Group Diabetes Program (UGDP), did not find a reduction of cardiovascular endpoints through improvement of metabolic control. The theoretical benefits of newer Insulin analogues might result in fewer macrovascular and microvascular events. Objectives To assess the effects of long-term treatment with long-acting Insulin analogues (Insulin glargine and Insulin detemir) compared to NPH Insulin in patients with type 2 diabetes mellitus. Search methods Studies were obtained from computerised searches of MEDLINE, EMBASE, The Cochrane Library and communication with experts in the field as well as Insulin producing companies. Selection criteria Studies were included if they were randomised controlled trials in adults with diabetes mellitus type 2 and had a trial duration of at least 24 weeks. Data collection and analysis Two authors independently assessed trial quality and extracted data. Pooling of studies by means of random-effects meta-analyses was performed. Main results Six studies comparing Insulin glargine to NPH (Neutral Protamine Hagedorn) Insulin and two studies comparing Insulin detemir to NPH Insulin were identified. In these trials, 1715 patients were randomised to Insulin glargine and 578 patients to Insulin detemir. Duration of the included trials ranged from 24 to 52 weeks. Metabolic control, measured by glycosylated haemoglobin A1c (HbA1c) as a surrogate endpoint, and adverse effects did not differ in a clinical relevant way between treatment groups. While no statistically significant difference for severe hypoglycaemia rates was shown in any of the trials, the rate of symptomatic, overall and nocturnal hypoglycaemia was statistically significantly lower in patients treated with either Insulin glargine or detemir. No evidence for a beneficial effect of long-acting analogues on patient-oriented outcomes like mortality, morbidity, quality of life or costs could be obtained. Authors' conclusions Our analysis suggests, if at all only a minor clinical benefit of treatment with long-acting Insulin analogues for patients with diabetes mellitus type 2 treated with "basal" Insulin regarding symptomatic nocturnal hypoglycaemic events. Until long-term efficacy and safety data are available, we suggest a cautious approach to therapy with Insulin glargine or detemir.
Andrea Siebenhofer - One of the best experts on this subject based on the ideXlab platform.
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(Ultra-)long-acting Insulin analogues versus NPH Insulin (human Isophane Insulin) for adults with type 2 diabetes mellitus.
The Cochrane database of systematic reviews, 2020Co-Authors: Thomas Semlitsch, Jennifer Engler, Andrea Siebenhofer, Klaus Jeitler, Andrea Berghold, Karl HorvathAbstract:Evidence that antihyperglycaemic therapy is beneficial for people with type 2 diabetes mellitus is conflicting. While the United Kingdom Prospective Diabetes Study (UKPDS) found tighter glycaemic control to be positive, other studies, such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, found the effects of an intensive therapy to lower blood glucose to near normal levels to be more harmful than beneficial. Study results also showed different effects for different antihyperglycaemic drugs, regardless of the achieved blood glucose levels. In consequence, firm conclusions on the effect of interventions on patient-relevant outcomes cannot be drawn from the effect of these interventions on blood glucose concentration alone. In theory, the use of newer Insulin analogues may result in fewer macrovascular and microvascular events. To compare the effects of long-term treatment with (ultra-)long-acting Insulin analogues (Insulin glargine U100 and U300, Insulin detemir and Insulin degludec) with NPH (neutral protamine Hagedorn) Insulin (human Isophane Insulin) in adults with type 2 diabetes mellitus. For this Cochrane Review update, we searched CENTRAL, MEDLINE, Embase, ICTRP Search Portal and ClinicalTrials.gov. The date of the last search was 5 November 2019, except Embase which was last searched 26 January 2017. We applied no language restrictions. We included randomised controlled trials (RCTs) comparing the effects of treatment with (ultra-)long-acting Insulin analogues to NPH in adults with type 2 diabetes mellitus. Two review authors independently selected trials, assessed risk of bias, extracted data and evaluated the overall certainty of the evidence using GRADE. Trials were pooled using random-effects meta-analyses. We identified 24 RCTs. Of these, 16 trials compared Insulin glargine to NPH Insulin and eight trials compared Insulin detemir to NPH Insulin. In these trials, 3419 people with type 2 diabetes mellitus were randomised to Insulin glargine and 1321 people to Insulin detemir. The duration of the included trials ranged from 24 weeks to five years. For studies, comparing Insulin glargine to NPH Insulin, target values ranged from 4.0 mmol/L to 7.8 mmol/L (72 mg/dL to 140 mg/dL) for fasting blood glucose (FBG), from 4.4 mmol/L to 6.6 mmol/L (80 mg/dL to 120 mg/dL) for nocturnal blood glucose and less than 10 mmol/L (180 mg/dL) for postprandial blood glucose, when applicable. Blood glucose and glycosylated haemoglobin A1c (HbA1c) target values for studies comparing Insulin detemir to NPH Insulin ranged from 4.0 mmol/L to 7.0 mmol/L (72 mg/dL to 126 mg/dL) for FBG, less than 6.7 mmol/L (120 mg/dL) to less than 10 mmol/L (180 mg/dL) for postprandial blood glucose, 4.0 mmol/L to 7.0 mmol/L (72 mg/dL to 126 mg/dL) for nocturnal blood glucose and 5.8% to less than 6.4% HbA1c, when applicable. All trials had an unclear or high risk of bias for several risk of bias domains. Overall, Insulin glargine and Insulin detemir resulted in fewer participants experiencing hypoglycaemia when compared with NPH Insulin. Changes in HbA1c were comparable for long-acting Insulin analogues and NPH Insulin. Insulin glargine compared to NPH Insulin had a risk ratio (RR) for severe hypoglycaemia of 0.68 (95% confidence interval (CI) 0.46 to 1.01; P = 0.06; absolute risk reduction (ARR) -1.2%, 95% CI -2.0 to 0; 14 trials, 6164 participants; very low-certainty evidence). The RR for serious hypoglycaemia was 0.75 (95% CI 0.52 to 1.09; P = 0.13; ARR -0.7%, 95% CI -1.3 to 0.2; 10 trials, 4685 participants; low-certainty evidence). Treatment with Insulin glargine reduced the incidence of confirmed hypoglycaemia and confirmed nocturnal hypoglycaemia. Treatment with Insulin detemir compared to NPH Insulin found an RR for severe hypoglycaemia of 0.45 (95% CI 0.17 to 1.20; P = 0.11; ARR -0.9%, 95% CI -1.4 to 0.4; 5 trials, 1804 participants; very low-certainty evidence). The Peto odds ratio for serious hypoglycaemia was 0.16, 95% CI 0.04 to 0.61; P = 0.007; ARR -0.9%, 95% CI -1.1 to -0.4; 5 trials, 1777 participants; low-certainty evidence). Treatment with detemir also reduced the incidence of confirmed hypoglycaemia and confirmed nocturnal hypoglycaemia. Information on patient-relevant outcomes such as death from any cause, diabetes-related complications, health-related quality of life and socioeconomic effects was insufficient or lacking in almost all included trials. For those outcomes for which some data were available, there were no meaningful differences between treatment with glargine or detemir and treatment with NPH. There was no clear difference between Insulin-analogues and NPH Insulin in terms of weight gain. The incidence of adverse events was comparable for people treated with glargine or detemir, and people treated with NPH. We found no trials comparing ultra-long-acting Insulin glargine U300 or Insulin degludec with NPH Insulin. While the effects on HbA1c were comparable, treatment with Insulin glargine and Insulin detemir resulted in fewer participants experiencing hypoglycaemia when compared with NPH Insulin. Treatment with Insulin detemir also reduced the incidence of serious hypoglycaemia. However, serious hypoglycaemic events were rare and the absolute risk reducing effect was low. Approximately one in 100 people treated with Insulin detemir instead of NPH Insulin benefited. In the studies, low blood glucose and HbA1c targets, corresponding to near normal or even non-diabetic blood glucose levels, were set. Therefore, results from the studies are only applicable to people in whom such low blood glucose concentrations are targeted. However, current guidelines recommend less-intensive blood glucose lowering for most people with type 2 diabetes in daily practice (e.g. people with cardiovascular diseases, a long history of type 2 diabetes, who are susceptible to hypoglycaemia or older people). Additionally, low-certainty evidence and trial designs that did not conform with current clinical practice meant it remains unclear if the same effects will be observed in daily clinical practice. Most trials did not report patient-relevant outcomes. Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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ultra long acting Insulin analogues versus nph Insulin human Isophane Insulin for adults with type 2 diabetes mellitus
Cochrane Database of Systematic Reviews, 2020Co-Authors: Thomas Semlitsch, Jennifer Engler, Andrea Siebenhofer, Klaus Jeitler, Andrea Berghold, Karl HorvathAbstract:Background Evidence that antihyperglycaemic therapy is beneficial for people with type 2 diabetes mellitus is conflicting. While the United Kingdom Prospective Diabetes Study (UKPDS) found tighter glycaemic control to be positive, other studies, such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, found the effects of an intensive therapy to lower blood glucose to near normal levels to be more harmful than beneficial. Study results also showed different effects for different antihyperglycaemic drugs, regardless of the achieved blood glucose levels. In consequence, firm conclusions on the effect of interventions on patient-relevant outcomes cannot be drawn from the effect of these interventions on blood glucose concentration alone. In theory, the use of newer Insulin analogues may result in fewer macrovascular and microvascular events. Objectives To compare the effects of long-term treatment with (ultra-)long-acting Insulin analogues (Insulin glargine U100 and U300, Insulin detemir and Insulin degludec) with NPH (neutral protamine Hagedorn) Insulin (human Isophane Insulin) in adults with type 2 diabetes mellitus. Search methods For this Cochrane Review update, we searched CENTRAL, MEDLINE, Embase, ICTRP Search Portal and ClinicalTrials.gov. The date of the last search was 5 November 2019, except Embase which was last searched 26 January 2017. We applied no language restrictions. Selection criteria We included randomised controlled trials (RCTs) comparing the effects of treatment with (ultra-)long-acting Insulin analogues to NPH in adults with type 2 diabetes mellitus. Data collection and analysis Two review authors independently selected trials, assessed risk of bias, extracted data and evaluated the overall certainty of the evidence using GRADE. Trials were pooled using random-effects meta-analyses. Main results We identified 24 RCTs. Of these, 16 trials compared Insulin glargine to NPH Insulin and eight trials compared Insulin detemir to NPH Insulin. In these trials, 3419 people with type 2 diabetes mellitus were randomised to Insulin glargine and 1321 people to Insulin detemir. The duration of the included trials ranged from 24 weeks to five years. For studies, comparing Insulin glargine to NPH Insulin, target values ranged from 4.0 mmol/L to 7.8 mmol/L (72 mg/dL to 140 mg/dL) for fasting blood glucose (FBG), from 4.4 mmol/L to 6.6 mmol/L (80 mg/dL to 120 mg/dL) for nocturnal blood glucose and less than 10 mmol/L (180 mg/dL) for postprandial blood glucose, when applicable. Blood glucose and glycosylated haemoglobin A1c (HbA1c) target values for studies comparing Insulin detemir to NPH Insulin ranged from 4.0 mmol/L to 7.0 mmol/L (72 mg/dL to 126 mg/dL) for FBG, less than 6.7 mmol/L (120 mg/dL) to less than 10 mmol/L (180 mg/dL) for postprandial blood glucose, 4.0 mmol/L to 7.0 mmol/L (72 mg/dL to 126 mg/dL) for nocturnal blood glucose and 5.8% to less than 6.4% HbA1c, when applicable. All trials had an unclear or high risk of bias for several risk of bias domains. Overall, Insulin glargine and Insulin detemir resulted in fewer participants experiencing hypoglycaemia when compared with NPH Insulin. Changes in HbA1c were comparable for long-acting Insulin analogues and NPH Insulin. Insulin glargine compared to NPH Insulin had a risk ratio (RR) for severe hypoglycaemia of 0.68 (95% confidence interval (CI) 0.46 to 1.01; P = 0.06; absolute risk reduction (ARR) -1.2%, 95% CI -2.0 to 0; 14 trials, 6164 participants; very low-certainty evidence). The RR for serious hypoglycaemia was 0.75 (95% CI 0.52 to 1.09; P = 0.13; ARR -0.7%, 95% CI -1.3 to 0.2; 10 trials, 4685 participants; low-certainty evidence). Treatment with Insulin glargine reduced the incidence of confirmed hypoglycaemia and confirmed nocturnal hypoglycaemia. Treatment with Insulin detemir compared to NPH Insulin found an RR for severe hypoglycaemia of 0.45 (95% CI 0.17 to 1.20; P = 0.11; ARR -0.9%, 95% CI -1.4 to 0.4; 5 trials, 1804 participants; very low-certainty evidence). The Peto odds ratio for serious hypoglycaemia was 0.16, 95% CI 0.04 to 0.61; P = 0.007; ARR -0.9%, 95% CI -1.1 to -0.4; 5 trials, 1777 participants; low-certainty evidence). Treatment with detemir also reduced the incidence of confirmed hypoglycaemia and confirmed nocturnal hypoglycaemia. Information on patient-relevant outcomes such as death from any cause, diabetes-related complications, health-related quality of life and socioeconomic effects was insufficient or lacking in almost all included trials. For those outcomes for which some data were available, there were no meaningful differences between treatment with glargine or detemir and treatment with NPH. There was no clear difference between Insulin-analogues and NPH Insulin in terms of weight gain. The incidence of adverse events was comparable for people treated with glargine or detemir, and people treated with NPH. We found no trials comparing ultra-long-acting Insulin glargine U300 or Insulin degludec with NPH Insulin. Authors' conclusions While the effects on HbA1c were comparable, treatment with Insulin glargine and Insulin detemir resulted in fewer participants experiencing hypoglycaemia when compared with NPH Insulin. Treatment with Insulin detemir also reduced the incidence of serious hypoglycaemia. However, serious hypoglycaemic events were rare and the absolute risk reducing effect was low. Approximately one in 100 people treated with Insulin detemir instead of NPH Insulin benefited. In the studies, low blood glucose and HbA1c targets, corresponding to near normal or even non-diabetic blood glucose levels, were set. Therefore, results from the studies are only applicable to people in whom such low blood glucose concentrations are targeted. However, current guidelines recommend less-intensive blood glucose lowering for most people with type 2 diabetes in daily practice (e.g. people with cardiovascular diseases, a long history of type 2 diabetes, who are susceptible to hypoglycaemia or older people). Additionally, low-certainty evidence and trial designs that did not conform with current clinical practice meant it remains unclear if the same effects will be observed in daily clinical practice. Most trials did not report patient-relevant outcomes.
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long acting Insulin analogues versus nph Insulin human Isophane Insulin for type 2 diabetes mellitus
Cochrane Database of Systematic Reviews, 2007Co-Authors: Karl Horvath, Klaus Jeitler, Andrea Berghold, Susanne H Ebrahim, Thomas W Gratzer, Johannes Plank, Thomas Kaiser, Thomas R Pieber, Andrea SiebenhoferAbstract:Background Despite indications from epidemiological trials that higher blood glucose concentrations are associated with a higher risk for developing micro- and macrovascular complications, evidence for a beneficial effect of antihyperglycaemic therapy in patients with type 2 diabetes mellitus is conflicting. Two large studies, the United Kingdom Prospective Diabetes Study (UKPDS) and the University Group Diabetes Program (UGDP), did not find a reduction of cardiovascular endpoints through improvement of metabolic control. The theoretical benefits of newer Insulin analogues might result in fewer macrovascular and microvascular events. Objectives To assess the effects of long-term treatment with long-acting Insulin analogues (Insulin glargine and Insulin detemir) compared to NPH Insulin in patients with type 2 diabetes mellitus. Search methods Studies were obtained from computerised searches of MEDLINE, EMBASE, The Cochrane Library and communication with experts in the field as well as Insulin producing companies. Selection criteria Studies were included if they were randomised controlled trials in adults with diabetes mellitus type 2 and had a trial duration of at least 24 weeks. Data collection and analysis Two authors independently assessed trial quality and extracted data. Pooling of studies by means of random-effects meta-analyses was performed. Main results Six studies comparing Insulin glargine to NPH (Neutral Protamine Hagedorn) Insulin and two studies comparing Insulin detemir to NPH Insulin were identified. In these trials, 1715 patients were randomised to Insulin glargine and 578 patients to Insulin detemir. Duration of the included trials ranged from 24 to 52 weeks. Metabolic control, measured by glycosylated haemoglobin A1c (HbA1c) as a surrogate endpoint, and adverse effects did not differ in a clinical relevant way between treatment groups. While no statistically significant difference for severe hypoglycaemia rates was shown in any of the trials, the rate of symptomatic, overall and nocturnal hypoglycaemia was statistically significantly lower in patients treated with either Insulin glargine or detemir. No evidence for a beneficial effect of long-acting analogues on patient-oriented outcomes like mortality, morbidity, quality of life or costs could be obtained. Authors' conclusions Our analysis suggests, if at all only a minor clinical benefit of treatment with long-acting Insulin analogues for patients with diabetes mellitus type 2 treated with "basal" Insulin regarding symptomatic nocturnal hypoglycaemic events. Until long-term efficacy and safety data are available, we suggest a cautious approach to therapy with Insulin glargine or detemir.
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The Cochrane Library - Long acting Insulin analogues versus NPH Insulin (human Isophane Insulin) for type 2 diabetes mellitus
The Cochrane database of systematic reviews, 2007Co-Authors: Karl Horvath, Klaus Jeitler, Andrea Berghold, Susanne H Ebrahim, Thomas W Gratzer, Johannes Plank, Thomas Kaiser, Thomas R Pieber, Andrea SiebenhoferAbstract:Background Despite indications from epidemiological trials that higher blood glucose concentrations are associated with a higher risk for developing micro- and macrovascular complications, evidence for a beneficial effect of antihyperglycaemic therapy in patients with type 2 diabetes mellitus is conflicting. Two large studies, the United Kingdom Prospective Diabetes Study (UKPDS) and the University Group Diabetes Program (UGDP), did not find a reduction of cardiovascular endpoints through improvement of metabolic control. The theoretical benefits of newer Insulin analogues might result in fewer macrovascular and microvascular events. Objectives To assess the effects of long-term treatment with long-acting Insulin analogues (Insulin glargine and Insulin detemir) compared to NPH Insulin in patients with type 2 diabetes mellitus. Search methods Studies were obtained from computerised searches of MEDLINE, EMBASE, The Cochrane Library and communication with experts in the field as well as Insulin producing companies. Selection criteria Studies were included if they were randomised controlled trials in adults with diabetes mellitus type 2 and had a trial duration of at least 24 weeks. Data collection and analysis Two authors independently assessed trial quality and extracted data. Pooling of studies by means of random-effects meta-analyses was performed. Main results Six studies comparing Insulin glargine to NPH (Neutral Protamine Hagedorn) Insulin and two studies comparing Insulin detemir to NPH Insulin were identified. In these trials, 1715 patients were randomised to Insulin glargine and 578 patients to Insulin detemir. Duration of the included trials ranged from 24 to 52 weeks. Metabolic control, measured by glycosylated haemoglobin A1c (HbA1c) as a surrogate endpoint, and adverse effects did not differ in a clinical relevant way between treatment groups. While no statistically significant difference for severe hypoglycaemia rates was shown in any of the trials, the rate of symptomatic, overall and nocturnal hypoglycaemia was statistically significantly lower in patients treated with either Insulin glargine or detemir. No evidence for a beneficial effect of long-acting analogues on patient-oriented outcomes like mortality, morbidity, quality of life or costs could be obtained. Authors' conclusions Our analysis suggests, if at all only a minor clinical benefit of treatment with long-acting Insulin analogues for patients with diabetes mellitus type 2 treated with "basal" Insulin regarding symptomatic nocturnal hypoglycaemic events. Until long-term efficacy and safety data are available, we suggest a cautious approach to therapy with Insulin glargine or detemir.
Andrea Berghold - One of the best experts on this subject based on the ideXlab platform.
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(Ultra-)long-acting Insulin analogues versus NPH Insulin (human Isophane Insulin) for adults with type 2 diabetes mellitus.
The Cochrane database of systematic reviews, 2020Co-Authors: Thomas Semlitsch, Jennifer Engler, Andrea Siebenhofer, Klaus Jeitler, Andrea Berghold, Karl HorvathAbstract:Evidence that antihyperglycaemic therapy is beneficial for people with type 2 diabetes mellitus is conflicting. While the United Kingdom Prospective Diabetes Study (UKPDS) found tighter glycaemic control to be positive, other studies, such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, found the effects of an intensive therapy to lower blood glucose to near normal levels to be more harmful than beneficial. Study results also showed different effects for different antihyperglycaemic drugs, regardless of the achieved blood glucose levels. In consequence, firm conclusions on the effect of interventions on patient-relevant outcomes cannot be drawn from the effect of these interventions on blood glucose concentration alone. In theory, the use of newer Insulin analogues may result in fewer macrovascular and microvascular events. To compare the effects of long-term treatment with (ultra-)long-acting Insulin analogues (Insulin glargine U100 and U300, Insulin detemir and Insulin degludec) with NPH (neutral protamine Hagedorn) Insulin (human Isophane Insulin) in adults with type 2 diabetes mellitus. For this Cochrane Review update, we searched CENTRAL, MEDLINE, Embase, ICTRP Search Portal and ClinicalTrials.gov. The date of the last search was 5 November 2019, except Embase which was last searched 26 January 2017. We applied no language restrictions. We included randomised controlled trials (RCTs) comparing the effects of treatment with (ultra-)long-acting Insulin analogues to NPH in adults with type 2 diabetes mellitus. Two review authors independently selected trials, assessed risk of bias, extracted data and evaluated the overall certainty of the evidence using GRADE. Trials were pooled using random-effects meta-analyses. We identified 24 RCTs. Of these, 16 trials compared Insulin glargine to NPH Insulin and eight trials compared Insulin detemir to NPH Insulin. In these trials, 3419 people with type 2 diabetes mellitus were randomised to Insulin glargine and 1321 people to Insulin detemir. The duration of the included trials ranged from 24 weeks to five years. For studies, comparing Insulin glargine to NPH Insulin, target values ranged from 4.0 mmol/L to 7.8 mmol/L (72 mg/dL to 140 mg/dL) for fasting blood glucose (FBG), from 4.4 mmol/L to 6.6 mmol/L (80 mg/dL to 120 mg/dL) for nocturnal blood glucose and less than 10 mmol/L (180 mg/dL) for postprandial blood glucose, when applicable. Blood glucose and glycosylated haemoglobin A1c (HbA1c) target values for studies comparing Insulin detemir to NPH Insulin ranged from 4.0 mmol/L to 7.0 mmol/L (72 mg/dL to 126 mg/dL) for FBG, less than 6.7 mmol/L (120 mg/dL) to less than 10 mmol/L (180 mg/dL) for postprandial blood glucose, 4.0 mmol/L to 7.0 mmol/L (72 mg/dL to 126 mg/dL) for nocturnal blood glucose and 5.8% to less than 6.4% HbA1c, when applicable. All trials had an unclear or high risk of bias for several risk of bias domains. Overall, Insulin glargine and Insulin detemir resulted in fewer participants experiencing hypoglycaemia when compared with NPH Insulin. Changes in HbA1c were comparable for long-acting Insulin analogues and NPH Insulin. Insulin glargine compared to NPH Insulin had a risk ratio (RR) for severe hypoglycaemia of 0.68 (95% confidence interval (CI) 0.46 to 1.01; P = 0.06; absolute risk reduction (ARR) -1.2%, 95% CI -2.0 to 0; 14 trials, 6164 participants; very low-certainty evidence). The RR for serious hypoglycaemia was 0.75 (95% CI 0.52 to 1.09; P = 0.13; ARR -0.7%, 95% CI -1.3 to 0.2; 10 trials, 4685 participants; low-certainty evidence). Treatment with Insulin glargine reduced the incidence of confirmed hypoglycaemia and confirmed nocturnal hypoglycaemia. Treatment with Insulin detemir compared to NPH Insulin found an RR for severe hypoglycaemia of 0.45 (95% CI 0.17 to 1.20; P = 0.11; ARR -0.9%, 95% CI -1.4 to 0.4; 5 trials, 1804 participants; very low-certainty evidence). The Peto odds ratio for serious hypoglycaemia was 0.16, 95% CI 0.04 to 0.61; P = 0.007; ARR -0.9%, 95% CI -1.1 to -0.4; 5 trials, 1777 participants; low-certainty evidence). Treatment with detemir also reduced the incidence of confirmed hypoglycaemia and confirmed nocturnal hypoglycaemia. Information on patient-relevant outcomes such as death from any cause, diabetes-related complications, health-related quality of life and socioeconomic effects was insufficient or lacking in almost all included trials. For those outcomes for which some data were available, there were no meaningful differences between treatment with glargine or detemir and treatment with NPH. There was no clear difference between Insulin-analogues and NPH Insulin in terms of weight gain. The incidence of adverse events was comparable for people treated with glargine or detemir, and people treated with NPH. We found no trials comparing ultra-long-acting Insulin glargine U300 or Insulin degludec with NPH Insulin. While the effects on HbA1c were comparable, treatment with Insulin glargine and Insulin detemir resulted in fewer participants experiencing hypoglycaemia when compared with NPH Insulin. Treatment with Insulin detemir also reduced the incidence of serious hypoglycaemia. However, serious hypoglycaemic events were rare and the absolute risk reducing effect was low. Approximately one in 100 people treated with Insulin detemir instead of NPH Insulin benefited. In the studies, low blood glucose and HbA1c targets, corresponding to near normal or even non-diabetic blood glucose levels, were set. Therefore, results from the studies are only applicable to people in whom such low blood glucose concentrations are targeted. However, current guidelines recommend less-intensive blood glucose lowering for most people with type 2 diabetes in daily practice (e.g. people with cardiovascular diseases, a long history of type 2 diabetes, who are susceptible to hypoglycaemia or older people). Additionally, low-certainty evidence and trial designs that did not conform with current clinical practice meant it remains unclear if the same effects will be observed in daily clinical practice. Most trials did not report patient-relevant outcomes. Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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ultra long acting Insulin analogues versus nph Insulin human Isophane Insulin for adults with type 2 diabetes mellitus
Cochrane Database of Systematic Reviews, 2020Co-Authors: Thomas Semlitsch, Jennifer Engler, Andrea Siebenhofer, Klaus Jeitler, Andrea Berghold, Karl HorvathAbstract:Background Evidence that antihyperglycaemic therapy is beneficial for people with type 2 diabetes mellitus is conflicting. While the United Kingdom Prospective Diabetes Study (UKPDS) found tighter glycaemic control to be positive, other studies, such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, found the effects of an intensive therapy to lower blood glucose to near normal levels to be more harmful than beneficial. Study results also showed different effects for different antihyperglycaemic drugs, regardless of the achieved blood glucose levels. In consequence, firm conclusions on the effect of interventions on patient-relevant outcomes cannot be drawn from the effect of these interventions on blood glucose concentration alone. In theory, the use of newer Insulin analogues may result in fewer macrovascular and microvascular events. Objectives To compare the effects of long-term treatment with (ultra-)long-acting Insulin analogues (Insulin glargine U100 and U300, Insulin detemir and Insulin degludec) with NPH (neutral protamine Hagedorn) Insulin (human Isophane Insulin) in adults with type 2 diabetes mellitus. Search methods For this Cochrane Review update, we searched CENTRAL, MEDLINE, Embase, ICTRP Search Portal and ClinicalTrials.gov. The date of the last search was 5 November 2019, except Embase which was last searched 26 January 2017. We applied no language restrictions. Selection criteria We included randomised controlled trials (RCTs) comparing the effects of treatment with (ultra-)long-acting Insulin analogues to NPH in adults with type 2 diabetes mellitus. Data collection and analysis Two review authors independently selected trials, assessed risk of bias, extracted data and evaluated the overall certainty of the evidence using GRADE. Trials were pooled using random-effects meta-analyses. Main results We identified 24 RCTs. Of these, 16 trials compared Insulin glargine to NPH Insulin and eight trials compared Insulin detemir to NPH Insulin. In these trials, 3419 people with type 2 diabetes mellitus were randomised to Insulin glargine and 1321 people to Insulin detemir. The duration of the included trials ranged from 24 weeks to five years. For studies, comparing Insulin glargine to NPH Insulin, target values ranged from 4.0 mmol/L to 7.8 mmol/L (72 mg/dL to 140 mg/dL) for fasting blood glucose (FBG), from 4.4 mmol/L to 6.6 mmol/L (80 mg/dL to 120 mg/dL) for nocturnal blood glucose and less than 10 mmol/L (180 mg/dL) for postprandial blood glucose, when applicable. Blood glucose and glycosylated haemoglobin A1c (HbA1c) target values for studies comparing Insulin detemir to NPH Insulin ranged from 4.0 mmol/L to 7.0 mmol/L (72 mg/dL to 126 mg/dL) for FBG, less than 6.7 mmol/L (120 mg/dL) to less than 10 mmol/L (180 mg/dL) for postprandial blood glucose, 4.0 mmol/L to 7.0 mmol/L (72 mg/dL to 126 mg/dL) for nocturnal blood glucose and 5.8% to less than 6.4% HbA1c, when applicable. All trials had an unclear or high risk of bias for several risk of bias domains. Overall, Insulin glargine and Insulin detemir resulted in fewer participants experiencing hypoglycaemia when compared with NPH Insulin. Changes in HbA1c were comparable for long-acting Insulin analogues and NPH Insulin. Insulin glargine compared to NPH Insulin had a risk ratio (RR) for severe hypoglycaemia of 0.68 (95% confidence interval (CI) 0.46 to 1.01; P = 0.06; absolute risk reduction (ARR) -1.2%, 95% CI -2.0 to 0; 14 trials, 6164 participants; very low-certainty evidence). The RR for serious hypoglycaemia was 0.75 (95% CI 0.52 to 1.09; P = 0.13; ARR -0.7%, 95% CI -1.3 to 0.2; 10 trials, 4685 participants; low-certainty evidence). Treatment with Insulin glargine reduced the incidence of confirmed hypoglycaemia and confirmed nocturnal hypoglycaemia. Treatment with Insulin detemir compared to NPH Insulin found an RR for severe hypoglycaemia of 0.45 (95% CI 0.17 to 1.20; P = 0.11; ARR -0.9%, 95% CI -1.4 to 0.4; 5 trials, 1804 participants; very low-certainty evidence). The Peto odds ratio for serious hypoglycaemia was 0.16, 95% CI 0.04 to 0.61; P = 0.007; ARR -0.9%, 95% CI -1.1 to -0.4; 5 trials, 1777 participants; low-certainty evidence). Treatment with detemir also reduced the incidence of confirmed hypoglycaemia and confirmed nocturnal hypoglycaemia. Information on patient-relevant outcomes such as death from any cause, diabetes-related complications, health-related quality of life and socioeconomic effects was insufficient or lacking in almost all included trials. For those outcomes for which some data were available, there were no meaningful differences between treatment with glargine or detemir and treatment with NPH. There was no clear difference between Insulin-analogues and NPH Insulin in terms of weight gain. The incidence of adverse events was comparable for people treated with glargine or detemir, and people treated with NPH. We found no trials comparing ultra-long-acting Insulin glargine U300 or Insulin degludec with NPH Insulin. Authors' conclusions While the effects on HbA1c were comparable, treatment with Insulin glargine and Insulin detemir resulted in fewer participants experiencing hypoglycaemia when compared with NPH Insulin. Treatment with Insulin detemir also reduced the incidence of serious hypoglycaemia. However, serious hypoglycaemic events were rare and the absolute risk reducing effect was low. Approximately one in 100 people treated with Insulin detemir instead of NPH Insulin benefited. In the studies, low blood glucose and HbA1c targets, corresponding to near normal or even non-diabetic blood glucose levels, were set. Therefore, results from the studies are only applicable to people in whom such low blood glucose concentrations are targeted. However, current guidelines recommend less-intensive blood glucose lowering for most people with type 2 diabetes in daily practice (e.g. people with cardiovascular diseases, a long history of type 2 diabetes, who are susceptible to hypoglycaemia or older people). Additionally, low-certainty evidence and trial designs that did not conform with current clinical practice meant it remains unclear if the same effects will be observed in daily clinical practice. Most trials did not report patient-relevant outcomes.
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long acting Insulin analogues versus nph Insulin human Isophane Insulin for type 2 diabetes mellitus
Cochrane Database of Systematic Reviews, 2007Co-Authors: Karl Horvath, Klaus Jeitler, Andrea Berghold, Susanne H Ebrahim, Thomas W Gratzer, Johannes Plank, Thomas Kaiser, Thomas R Pieber, Andrea SiebenhoferAbstract:Background Despite indications from epidemiological trials that higher blood glucose concentrations are associated with a higher risk for developing micro- and macrovascular complications, evidence for a beneficial effect of antihyperglycaemic therapy in patients with type 2 diabetes mellitus is conflicting. Two large studies, the United Kingdom Prospective Diabetes Study (UKPDS) and the University Group Diabetes Program (UGDP), did not find a reduction of cardiovascular endpoints through improvement of metabolic control. The theoretical benefits of newer Insulin analogues might result in fewer macrovascular and microvascular events. Objectives To assess the effects of long-term treatment with long-acting Insulin analogues (Insulin glargine and Insulin detemir) compared to NPH Insulin in patients with type 2 diabetes mellitus. Search methods Studies were obtained from computerised searches of MEDLINE, EMBASE, The Cochrane Library and communication with experts in the field as well as Insulin producing companies. Selection criteria Studies were included if they were randomised controlled trials in adults with diabetes mellitus type 2 and had a trial duration of at least 24 weeks. Data collection and analysis Two authors independently assessed trial quality and extracted data. Pooling of studies by means of random-effects meta-analyses was performed. Main results Six studies comparing Insulin glargine to NPH (Neutral Protamine Hagedorn) Insulin and two studies comparing Insulin detemir to NPH Insulin were identified. In these trials, 1715 patients were randomised to Insulin glargine and 578 patients to Insulin detemir. Duration of the included trials ranged from 24 to 52 weeks. Metabolic control, measured by glycosylated haemoglobin A1c (HbA1c) as a surrogate endpoint, and adverse effects did not differ in a clinical relevant way between treatment groups. While no statistically significant difference for severe hypoglycaemia rates was shown in any of the trials, the rate of symptomatic, overall and nocturnal hypoglycaemia was statistically significantly lower in patients treated with either Insulin glargine or detemir. No evidence for a beneficial effect of long-acting analogues on patient-oriented outcomes like mortality, morbidity, quality of life or costs could be obtained. Authors' conclusions Our analysis suggests, if at all only a minor clinical benefit of treatment with long-acting Insulin analogues for patients with diabetes mellitus type 2 treated with "basal" Insulin regarding symptomatic nocturnal hypoglycaemic events. Until long-term efficacy and safety data are available, we suggest a cautious approach to therapy with Insulin glargine or detemir.
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The Cochrane Library - Long acting Insulin analogues versus NPH Insulin (human Isophane Insulin) for type 2 diabetes mellitus
The Cochrane database of systematic reviews, 2007Co-Authors: Karl Horvath, Klaus Jeitler, Andrea Berghold, Susanne H Ebrahim, Thomas W Gratzer, Johannes Plank, Thomas Kaiser, Thomas R Pieber, Andrea SiebenhoferAbstract:Background Despite indications from epidemiological trials that higher blood glucose concentrations are associated with a higher risk for developing micro- and macrovascular complications, evidence for a beneficial effect of antihyperglycaemic therapy in patients with type 2 diabetes mellitus is conflicting. Two large studies, the United Kingdom Prospective Diabetes Study (UKPDS) and the University Group Diabetes Program (UGDP), did not find a reduction of cardiovascular endpoints through improvement of metabolic control. The theoretical benefits of newer Insulin analogues might result in fewer macrovascular and microvascular events. Objectives To assess the effects of long-term treatment with long-acting Insulin analogues (Insulin glargine and Insulin detemir) compared to NPH Insulin in patients with type 2 diabetes mellitus. Search methods Studies were obtained from computerised searches of MEDLINE, EMBASE, The Cochrane Library and communication with experts in the field as well as Insulin producing companies. Selection criteria Studies were included if they were randomised controlled trials in adults with diabetes mellitus type 2 and had a trial duration of at least 24 weeks. Data collection and analysis Two authors independently assessed trial quality and extracted data. Pooling of studies by means of random-effects meta-analyses was performed. Main results Six studies comparing Insulin glargine to NPH (Neutral Protamine Hagedorn) Insulin and two studies comparing Insulin detemir to NPH Insulin were identified. In these trials, 1715 patients were randomised to Insulin glargine and 578 patients to Insulin detemir. Duration of the included trials ranged from 24 to 52 weeks. Metabolic control, measured by glycosylated haemoglobin A1c (HbA1c) as a surrogate endpoint, and adverse effects did not differ in a clinical relevant way between treatment groups. While no statistically significant difference for severe hypoglycaemia rates was shown in any of the trials, the rate of symptomatic, overall and nocturnal hypoglycaemia was statistically significantly lower in patients treated with either Insulin glargine or detemir. No evidence for a beneficial effect of long-acting analogues on patient-oriented outcomes like mortality, morbidity, quality of life or costs could be obtained. Authors' conclusions Our analysis suggests, if at all only a minor clinical benefit of treatment with long-acting Insulin analogues for patients with diabetes mellitus type 2 treated with "basal" Insulin regarding symptomatic nocturnal hypoglycaemic events. Until long-term efficacy and safety data are available, we suggest a cautious approach to therapy with Insulin glargine or detemir.
Klaus Jeitler - One of the best experts on this subject based on the ideXlab platform.
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(Ultra-)long-acting Insulin analogues versus NPH Insulin (human Isophane Insulin) for adults with type 2 diabetes mellitus.
The Cochrane database of systematic reviews, 2020Co-Authors: Thomas Semlitsch, Jennifer Engler, Andrea Siebenhofer, Klaus Jeitler, Andrea Berghold, Karl HorvathAbstract:Evidence that antihyperglycaemic therapy is beneficial for people with type 2 diabetes mellitus is conflicting. While the United Kingdom Prospective Diabetes Study (UKPDS) found tighter glycaemic control to be positive, other studies, such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, found the effects of an intensive therapy to lower blood glucose to near normal levels to be more harmful than beneficial. Study results also showed different effects for different antihyperglycaemic drugs, regardless of the achieved blood glucose levels. In consequence, firm conclusions on the effect of interventions on patient-relevant outcomes cannot be drawn from the effect of these interventions on blood glucose concentration alone. In theory, the use of newer Insulin analogues may result in fewer macrovascular and microvascular events. To compare the effects of long-term treatment with (ultra-)long-acting Insulin analogues (Insulin glargine U100 and U300, Insulin detemir and Insulin degludec) with NPH (neutral protamine Hagedorn) Insulin (human Isophane Insulin) in adults with type 2 diabetes mellitus. For this Cochrane Review update, we searched CENTRAL, MEDLINE, Embase, ICTRP Search Portal and ClinicalTrials.gov. The date of the last search was 5 November 2019, except Embase which was last searched 26 January 2017. We applied no language restrictions. We included randomised controlled trials (RCTs) comparing the effects of treatment with (ultra-)long-acting Insulin analogues to NPH in adults with type 2 diabetes mellitus. Two review authors independently selected trials, assessed risk of bias, extracted data and evaluated the overall certainty of the evidence using GRADE. Trials were pooled using random-effects meta-analyses. We identified 24 RCTs. Of these, 16 trials compared Insulin glargine to NPH Insulin and eight trials compared Insulin detemir to NPH Insulin. In these trials, 3419 people with type 2 diabetes mellitus were randomised to Insulin glargine and 1321 people to Insulin detemir. The duration of the included trials ranged from 24 weeks to five years. For studies, comparing Insulin glargine to NPH Insulin, target values ranged from 4.0 mmol/L to 7.8 mmol/L (72 mg/dL to 140 mg/dL) for fasting blood glucose (FBG), from 4.4 mmol/L to 6.6 mmol/L (80 mg/dL to 120 mg/dL) for nocturnal blood glucose and less than 10 mmol/L (180 mg/dL) for postprandial blood glucose, when applicable. Blood glucose and glycosylated haemoglobin A1c (HbA1c) target values for studies comparing Insulin detemir to NPH Insulin ranged from 4.0 mmol/L to 7.0 mmol/L (72 mg/dL to 126 mg/dL) for FBG, less than 6.7 mmol/L (120 mg/dL) to less than 10 mmol/L (180 mg/dL) for postprandial blood glucose, 4.0 mmol/L to 7.0 mmol/L (72 mg/dL to 126 mg/dL) for nocturnal blood glucose and 5.8% to less than 6.4% HbA1c, when applicable. All trials had an unclear or high risk of bias for several risk of bias domains. Overall, Insulin glargine and Insulin detemir resulted in fewer participants experiencing hypoglycaemia when compared with NPH Insulin. Changes in HbA1c were comparable for long-acting Insulin analogues and NPH Insulin. Insulin glargine compared to NPH Insulin had a risk ratio (RR) for severe hypoglycaemia of 0.68 (95% confidence interval (CI) 0.46 to 1.01; P = 0.06; absolute risk reduction (ARR) -1.2%, 95% CI -2.0 to 0; 14 trials, 6164 participants; very low-certainty evidence). The RR for serious hypoglycaemia was 0.75 (95% CI 0.52 to 1.09; P = 0.13; ARR -0.7%, 95% CI -1.3 to 0.2; 10 trials, 4685 participants; low-certainty evidence). Treatment with Insulin glargine reduced the incidence of confirmed hypoglycaemia and confirmed nocturnal hypoglycaemia. Treatment with Insulin detemir compared to NPH Insulin found an RR for severe hypoglycaemia of 0.45 (95% CI 0.17 to 1.20; P = 0.11; ARR -0.9%, 95% CI -1.4 to 0.4; 5 trials, 1804 participants; very low-certainty evidence). The Peto odds ratio for serious hypoglycaemia was 0.16, 95% CI 0.04 to 0.61; P = 0.007; ARR -0.9%, 95% CI -1.1 to -0.4; 5 trials, 1777 participants; low-certainty evidence). Treatment with detemir also reduced the incidence of confirmed hypoglycaemia and confirmed nocturnal hypoglycaemia. Information on patient-relevant outcomes such as death from any cause, diabetes-related complications, health-related quality of life and socioeconomic effects was insufficient or lacking in almost all included trials. For those outcomes for which some data were available, there were no meaningful differences between treatment with glargine or detemir and treatment with NPH. There was no clear difference between Insulin-analogues and NPH Insulin in terms of weight gain. The incidence of adverse events was comparable for people treated with glargine or detemir, and people treated with NPH. We found no trials comparing ultra-long-acting Insulin glargine U300 or Insulin degludec with NPH Insulin. While the effects on HbA1c were comparable, treatment with Insulin glargine and Insulin detemir resulted in fewer participants experiencing hypoglycaemia when compared with NPH Insulin. Treatment with Insulin detemir also reduced the incidence of serious hypoglycaemia. However, serious hypoglycaemic events were rare and the absolute risk reducing effect was low. Approximately one in 100 people treated with Insulin detemir instead of NPH Insulin benefited. In the studies, low blood glucose and HbA1c targets, corresponding to near normal or even non-diabetic blood glucose levels, were set. Therefore, results from the studies are only applicable to people in whom such low blood glucose concentrations are targeted. However, current guidelines recommend less-intensive blood glucose lowering for most people with type 2 diabetes in daily practice (e.g. people with cardiovascular diseases, a long history of type 2 diabetes, who are susceptible to hypoglycaemia or older people). Additionally, low-certainty evidence and trial designs that did not conform with current clinical practice meant it remains unclear if the same effects will be observed in daily clinical practice. Most trials did not report patient-relevant outcomes. Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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ultra long acting Insulin analogues versus nph Insulin human Isophane Insulin for adults with type 2 diabetes mellitus
Cochrane Database of Systematic Reviews, 2020Co-Authors: Thomas Semlitsch, Jennifer Engler, Andrea Siebenhofer, Klaus Jeitler, Andrea Berghold, Karl HorvathAbstract:Background Evidence that antihyperglycaemic therapy is beneficial for people with type 2 diabetes mellitus is conflicting. While the United Kingdom Prospective Diabetes Study (UKPDS) found tighter glycaemic control to be positive, other studies, such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, found the effects of an intensive therapy to lower blood glucose to near normal levels to be more harmful than beneficial. Study results also showed different effects for different antihyperglycaemic drugs, regardless of the achieved blood glucose levels. In consequence, firm conclusions on the effect of interventions on patient-relevant outcomes cannot be drawn from the effect of these interventions on blood glucose concentration alone. In theory, the use of newer Insulin analogues may result in fewer macrovascular and microvascular events. Objectives To compare the effects of long-term treatment with (ultra-)long-acting Insulin analogues (Insulin glargine U100 and U300, Insulin detemir and Insulin degludec) with NPH (neutral protamine Hagedorn) Insulin (human Isophane Insulin) in adults with type 2 diabetes mellitus. Search methods For this Cochrane Review update, we searched CENTRAL, MEDLINE, Embase, ICTRP Search Portal and ClinicalTrials.gov. The date of the last search was 5 November 2019, except Embase which was last searched 26 January 2017. We applied no language restrictions. Selection criteria We included randomised controlled trials (RCTs) comparing the effects of treatment with (ultra-)long-acting Insulin analogues to NPH in adults with type 2 diabetes mellitus. Data collection and analysis Two review authors independently selected trials, assessed risk of bias, extracted data and evaluated the overall certainty of the evidence using GRADE. Trials were pooled using random-effects meta-analyses. Main results We identified 24 RCTs. Of these, 16 trials compared Insulin glargine to NPH Insulin and eight trials compared Insulin detemir to NPH Insulin. In these trials, 3419 people with type 2 diabetes mellitus were randomised to Insulin glargine and 1321 people to Insulin detemir. The duration of the included trials ranged from 24 weeks to five years. For studies, comparing Insulin glargine to NPH Insulin, target values ranged from 4.0 mmol/L to 7.8 mmol/L (72 mg/dL to 140 mg/dL) for fasting blood glucose (FBG), from 4.4 mmol/L to 6.6 mmol/L (80 mg/dL to 120 mg/dL) for nocturnal blood glucose and less than 10 mmol/L (180 mg/dL) for postprandial blood glucose, when applicable. Blood glucose and glycosylated haemoglobin A1c (HbA1c) target values for studies comparing Insulin detemir to NPH Insulin ranged from 4.0 mmol/L to 7.0 mmol/L (72 mg/dL to 126 mg/dL) for FBG, less than 6.7 mmol/L (120 mg/dL) to less than 10 mmol/L (180 mg/dL) for postprandial blood glucose, 4.0 mmol/L to 7.0 mmol/L (72 mg/dL to 126 mg/dL) for nocturnal blood glucose and 5.8% to less than 6.4% HbA1c, when applicable. All trials had an unclear or high risk of bias for several risk of bias domains. Overall, Insulin glargine and Insulin detemir resulted in fewer participants experiencing hypoglycaemia when compared with NPH Insulin. Changes in HbA1c were comparable for long-acting Insulin analogues and NPH Insulin. Insulin glargine compared to NPH Insulin had a risk ratio (RR) for severe hypoglycaemia of 0.68 (95% confidence interval (CI) 0.46 to 1.01; P = 0.06; absolute risk reduction (ARR) -1.2%, 95% CI -2.0 to 0; 14 trials, 6164 participants; very low-certainty evidence). The RR for serious hypoglycaemia was 0.75 (95% CI 0.52 to 1.09; P = 0.13; ARR -0.7%, 95% CI -1.3 to 0.2; 10 trials, 4685 participants; low-certainty evidence). Treatment with Insulin glargine reduced the incidence of confirmed hypoglycaemia and confirmed nocturnal hypoglycaemia. Treatment with Insulin detemir compared to NPH Insulin found an RR for severe hypoglycaemia of 0.45 (95% CI 0.17 to 1.20; P = 0.11; ARR -0.9%, 95% CI -1.4 to 0.4; 5 trials, 1804 participants; very low-certainty evidence). The Peto odds ratio for serious hypoglycaemia was 0.16, 95% CI 0.04 to 0.61; P = 0.007; ARR -0.9%, 95% CI -1.1 to -0.4; 5 trials, 1777 participants; low-certainty evidence). Treatment with detemir also reduced the incidence of confirmed hypoglycaemia and confirmed nocturnal hypoglycaemia. Information on patient-relevant outcomes such as death from any cause, diabetes-related complications, health-related quality of life and socioeconomic effects was insufficient or lacking in almost all included trials. For those outcomes for which some data were available, there were no meaningful differences between treatment with glargine or detemir and treatment with NPH. There was no clear difference between Insulin-analogues and NPH Insulin in terms of weight gain. The incidence of adverse events was comparable for people treated with glargine or detemir, and people treated with NPH. We found no trials comparing ultra-long-acting Insulin glargine U300 or Insulin degludec with NPH Insulin. Authors' conclusions While the effects on HbA1c were comparable, treatment with Insulin glargine and Insulin detemir resulted in fewer participants experiencing hypoglycaemia when compared with NPH Insulin. Treatment with Insulin detemir also reduced the incidence of serious hypoglycaemia. However, serious hypoglycaemic events were rare and the absolute risk reducing effect was low. Approximately one in 100 people treated with Insulin detemir instead of NPH Insulin benefited. In the studies, low blood glucose and HbA1c targets, corresponding to near normal or even non-diabetic blood glucose levels, were set. Therefore, results from the studies are only applicable to people in whom such low blood glucose concentrations are targeted. However, current guidelines recommend less-intensive blood glucose lowering for most people with type 2 diabetes in daily practice (e.g. people with cardiovascular diseases, a long history of type 2 diabetes, who are susceptible to hypoglycaemia or older people). Additionally, low-certainty evidence and trial designs that did not conform with current clinical practice meant it remains unclear if the same effects will be observed in daily clinical practice. Most trials did not report patient-relevant outcomes.
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long acting Insulin analogues versus nph Insulin human Isophane Insulin for type 2 diabetes mellitus
Cochrane Database of Systematic Reviews, 2007Co-Authors: Karl Horvath, Klaus Jeitler, Andrea Berghold, Susanne H Ebrahim, Thomas W Gratzer, Johannes Plank, Thomas Kaiser, Thomas R Pieber, Andrea SiebenhoferAbstract:Background Despite indications from epidemiological trials that higher blood glucose concentrations are associated with a higher risk for developing micro- and macrovascular complications, evidence for a beneficial effect of antihyperglycaemic therapy in patients with type 2 diabetes mellitus is conflicting. Two large studies, the United Kingdom Prospective Diabetes Study (UKPDS) and the University Group Diabetes Program (UGDP), did not find a reduction of cardiovascular endpoints through improvement of metabolic control. The theoretical benefits of newer Insulin analogues might result in fewer macrovascular and microvascular events. Objectives To assess the effects of long-term treatment with long-acting Insulin analogues (Insulin glargine and Insulin detemir) compared to NPH Insulin in patients with type 2 diabetes mellitus. Search methods Studies were obtained from computerised searches of MEDLINE, EMBASE, The Cochrane Library and communication with experts in the field as well as Insulin producing companies. Selection criteria Studies were included if they were randomised controlled trials in adults with diabetes mellitus type 2 and had a trial duration of at least 24 weeks. Data collection and analysis Two authors independently assessed trial quality and extracted data. Pooling of studies by means of random-effects meta-analyses was performed. Main results Six studies comparing Insulin glargine to NPH (Neutral Protamine Hagedorn) Insulin and two studies comparing Insulin detemir to NPH Insulin were identified. In these trials, 1715 patients were randomised to Insulin glargine and 578 patients to Insulin detemir. Duration of the included trials ranged from 24 to 52 weeks. Metabolic control, measured by glycosylated haemoglobin A1c (HbA1c) as a surrogate endpoint, and adverse effects did not differ in a clinical relevant way between treatment groups. While no statistically significant difference for severe hypoglycaemia rates was shown in any of the trials, the rate of symptomatic, overall and nocturnal hypoglycaemia was statistically significantly lower in patients treated with either Insulin glargine or detemir. No evidence for a beneficial effect of long-acting analogues on patient-oriented outcomes like mortality, morbidity, quality of life or costs could be obtained. Authors' conclusions Our analysis suggests, if at all only a minor clinical benefit of treatment with long-acting Insulin analogues for patients with diabetes mellitus type 2 treated with "basal" Insulin regarding symptomatic nocturnal hypoglycaemic events. Until long-term efficacy and safety data are available, we suggest a cautious approach to therapy with Insulin glargine or detemir.
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The Cochrane Library - Long acting Insulin analogues versus NPH Insulin (human Isophane Insulin) for type 2 diabetes mellitus
The Cochrane database of systematic reviews, 2007Co-Authors: Karl Horvath, Klaus Jeitler, Andrea Berghold, Susanne H Ebrahim, Thomas W Gratzer, Johannes Plank, Thomas Kaiser, Thomas R Pieber, Andrea SiebenhoferAbstract:Background Despite indications from epidemiological trials that higher blood glucose concentrations are associated with a higher risk for developing micro- and macrovascular complications, evidence for a beneficial effect of antihyperglycaemic therapy in patients with type 2 diabetes mellitus is conflicting. Two large studies, the United Kingdom Prospective Diabetes Study (UKPDS) and the University Group Diabetes Program (UGDP), did not find a reduction of cardiovascular endpoints through improvement of metabolic control. The theoretical benefits of newer Insulin analogues might result in fewer macrovascular and microvascular events. Objectives To assess the effects of long-term treatment with long-acting Insulin analogues (Insulin glargine and Insulin detemir) compared to NPH Insulin in patients with type 2 diabetes mellitus. Search methods Studies were obtained from computerised searches of MEDLINE, EMBASE, The Cochrane Library and communication with experts in the field as well as Insulin producing companies. Selection criteria Studies were included if they were randomised controlled trials in adults with diabetes mellitus type 2 and had a trial duration of at least 24 weeks. Data collection and analysis Two authors independently assessed trial quality and extracted data. Pooling of studies by means of random-effects meta-analyses was performed. Main results Six studies comparing Insulin glargine to NPH (Neutral Protamine Hagedorn) Insulin and two studies comparing Insulin detemir to NPH Insulin were identified. In these trials, 1715 patients were randomised to Insulin glargine and 578 patients to Insulin detemir. Duration of the included trials ranged from 24 to 52 weeks. Metabolic control, measured by glycosylated haemoglobin A1c (HbA1c) as a surrogate endpoint, and adverse effects did not differ in a clinical relevant way between treatment groups. While no statistically significant difference for severe hypoglycaemia rates was shown in any of the trials, the rate of symptomatic, overall and nocturnal hypoglycaemia was statistically significantly lower in patients treated with either Insulin glargine or detemir. No evidence for a beneficial effect of long-acting analogues on patient-oriented outcomes like mortality, morbidity, quality of life or costs could be obtained. Authors' conclusions Our analysis suggests, if at all only a minor clinical benefit of treatment with long-acting Insulin analogues for patients with diabetes mellitus type 2 treated with "basal" Insulin regarding symptomatic nocturnal hypoglycaemic events. Until long-term efficacy and safety data are available, we suggest a cautious approach to therapy with Insulin glargine or detemir.
Manish Khanolkar - One of the best experts on this subject based on the ideXlab platform.
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Starting Insulin in Type 2 Diabetes: Real-World Outcomes After the First 12 Months of Insulin Therapy in a New Zealand Cohort
Diabetes Therapy, 2015Co-Authors: Shekhar Sehgal, Manish KhanolkarAbstract:Aims Currently, there is no consensus on which form of Insulin to use when initiating Insulin in type 2 diabetes (T2D). Our aim was to compare glycated hemoglobin (HbA1C) reduction, weight change and severe hypoglycemia rates during the first year after initiation of intermediate-acting Insulin Isophane, Insulin glargine and pre-mixed Insulin in patients with T2D. Methods Electronic clinical records of patients with T2D, starting Insulin at a tertiary referral center in Auckland, New Zealand, from January 1 to December 31, 2012, were retrospectively evaluated. Primary outcomes were HbA1C reduction at 12 months and number of hospital admissions for hypoglycemia. Results Of 339 eligible patients, 273 (80.5%) started on intermediate Insulin, 24 started on Insulin glargine and 42 started on pre-mixed Insulin. The mean HbA1C at Insulin initiation was 89–95 mmol/mol, but had decreased at 12 months by 26.6 mmol/mol with Insulin glargine, 23.4 mmol/mol with pre-mixed Insulin and 16.6 mmol/mol with Insulin Isophane ( p
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Erratum to: Starting Insulin in Type 2 Diabetes: Real-World Outcomes After the First 12 Months of Insulin Therapy in a New Zealand Cohort
Diabetes Therapy, 2015Co-Authors: Shekhar Sehgal, Manish KhanolkarAbstract:Aims Currently, there is no consensus on which form of Insulin to use when initiating Insulin in type 2 diabetes (T2D). Our aim was to compare glycated hemoglobin (HbA1C) reduction, weight change and severe hypoglycemia rates during the first year after initiation of intermediate-acting Insulin Isophane, Insulin glargine and pre-mixed Insulin in patients with T2D.
