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Journal ArticleDOI

The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.

30 Sep 1993-The New England Journal of Medicine (N Engl J Med)-Vol. 329, Iss: 14, pp 977-986

TL;DR: Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.
Abstract: Background Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications. Methods A total of 1441 patients with IDDM--726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly. Results In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of > or = 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of > or = 300 mg per 24 hours) by 54 percent (95 percent confidence interval 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia. Conclusions Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.
Topics: Insulin pump (56%), Type 1 diabetes (55%), Confidence interval (53%), Retinopathy (53%), Diabetes mellitus (52%)
Citations
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Journal ArticleDOI
13 Sep 1997-BMJ
TL;DR: Funnel plots, plots of the trials' effect estimates against sample size, are skewed and asymmetrical in the presence of publication bias and other biases Funnel plot asymmetry, measured by regression analysis, predicts discordance of results when meta-analyses are compared with single large trials.
Abstract: Objective: Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses. Design: Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30% of the trial); analysis of funnel plots from 37 meta-analyses identified from a hand search of four leading general medicine journals 1993-6 and 38 meta-analyses from the second 1996 issue of the Cochrane Database of Systematic Reviews . Main outcome measure: Degree of funnel plot asymmetry as measured by the intercept from regression of standard normal deviates against precision. Results: In the eight pairs of meta-analysis and large trial that were identified (five from cardiovascular medicine, one from diabetic medicine, one from geriatric medicine, one from perinatal medicine) there were four concordant and four discordant pairs. In all cases discordance was due to meta-analyses showing larger effects. Funnel plot asymmetry was present in three out of four discordant pairs but in none of concordant pairs. In 14 (38%) journal meta-analyses and 5 (13%) Cochrane reviews, funnel plot asymmetry indicated that there was bias. Conclusions: A simple analysis of funnel plots provides a useful test for the likely presence of bias in meta-analyses, but as the capacity to detect bias will be limited when meta-analyses are based on a limited number of small trials the results from such analyses should be treated with considerable caution. Key messages Systematic reviews of randomised trials are the best strategy for appraising evidence; however, the findings of some meta-analyses were later contradicted by large trials Funnel plots, plots of the trials9 effect estimates against sample size, are skewed and asymmetrical in the presence of publication bias and other biases Funnel plot asymmetry, measured by regression analysis, predicts discordance of results when meta-analyses are compared with single large trials Funnel plot asymmetry was found in 38% of meta-analyses published in leading general medicine journals and in 13% of reviews from the Cochrane Database of Systematic Reviews Critical examination of systematic reviews for publication and related biases should be considered a routine procedure

31,295 citations


Journal Article
12 Sep 1998-The Lancet
Abstract: Background Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial.Methods 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or. glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. in the conventional group, the aim was the best achievable FPG with diet atone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye,or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy.Findings Over 10 years, haemoglobin A(1c) (HbA(1c)) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group-an 11% reduction. There was no difference in HbA(1c) among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints the three intensive agents (chlorpropamide, glibenclamide, or insulin).Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg).Interpretation Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes. None of the individual drugs had an adverse effect on cardiovascular outcomes. All intensive treatment increased the risk of hypoglycaemia.

16,462 citations


Journal ArticleDOI
TL;DR: 2007 Guidelines for the Management of Arterial Hypertension : The Task Force for the management of Arterspertension of the European Society ofhypertension (ESH) and of theEuropean Society of Cardiology (ESC).
Abstract: 2007 Guidelines for the Management of Arterial Hypertension : The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).

9,819 citations


Journal ArticleDOI
TL;DR: Intensive insulin therapy to maintain blood glucose at or below 110 mg per deciliter reduces morbidity and mortality among critically ill patients in the surgical intensive care unit.
Abstract: Background Hyperglycemia and insulin resistance are common in critically ill patients, even if they have not previously had diabetes. Whether the normalization of blood glucose levels with insulin therapy improves the prognosis for such patients is not known. Methods We performed a prospective, randomized, controlled study involving adults admitted to our surgical intensive care unit who were receiving mechanical ventilation. On admission, patients were randomly assigned to receive intensive insulin therapy (maintenance of blood glucose at a level between 80 and 110 mg per deciliter) or conventional treatment (infusion of insulin only if the blood glucose level exceeded 215 mg per deciliter and maintenance of glucose at a level between 180 and 200 mg per deciliter). Results At 12 months, with a total of 1548 patients enrolled, intensive insulin therapy reduced mortality during intensive care from 8.0 percent with conventional treatment to 4.6 percent (P<0.04, with adjustment for sequential analyses). The ...

8,522 citations


Journal ArticleDOI
Michael Brownlee1Institutions (1)
13 Dec 2001-Nature
TL;DR: This integrating paradigm provides a new conceptual framework for future research and drug discovery in diabetes-specific microvascular disease and seems to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain.
Abstract: Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage, and diabetes-accelerated atherosclerosis leads to increased risk of myocardial infarction, stroke and limb amputation. Four main molecular mechanisms have been implicated in glucose-mediated vascular damage. All seem to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain. This integrating paradigm provides a new conceptual framework for future research and drug discovery.

7,765 citations


References
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Journal ArticleDOI
TL;DR: In a population-based study in southern Wisconsin, 996 insulin-taking, younger-onset diabetic persons were examined using standard protocols to determine the prevalence and severity of diabetic retinopathy and associated risk variables.
Abstract: In a population-based study in southern Wisconsin, 996 insulin-taking, younger-onset diabetic persons were examined using standard protocols to determine the prevalence and severity of diabetic retinopathy and associated risk variables. The prevalence of diabetic retinopathy varied from 17% to 97.5% in persons with diabetes for less than five years and 15 or more years, respectively. Proliferative retinopathy varied from 1.2% to 67% in persons with diabetes for less than ten years and 35 or more years, respectively. For persons with diabetes of 10 years' duration or less, the Cox regression model relates the severity or retinopathy to longer duration, older age at examination, and higher levels of glycosylated hemoglobin. After ten years of diabetes, severity of retinopathy was related to longer duration, high levels of glycosylated hemoglobin, presence of proteinuria, higher diastolic BP, and male sex.

1,825 citations


Journal ArticleDOI
TL;DR: The severity of retinopathy was found to be related to longer duration of diabetes, younger age at diagnosis, higher glycosylated hemoglobin levels, higher systolic BP, use of insulin, presence of proteinuria, and small body mass.
Abstract: • In a population-based study in southern Wisconsin, 1,370 patients given diagnoses of diabetes at age 30 years or older were examined using standard protocols to determine the prevalence and severity of diabetic retinopathy and associated risk variables. The prevalence of diabetic retinopathy varied from 28.8% in persons who had diabetes for less than five years to 77.8% in persons who had diabetes for 15 or more years. The rate of proliferative diabetic retinopathy varied from 2.0% in persons who had diabetes for less than five years to 15.5% in persons who had diabetes for 15 or more years. By using the Cox regression model, the severity of retinopathy was found to be related to longer duration of diabetes, younger age at diagnosis, higher glycosylated hemoglobin levels, higher systolic BP, use of insulin, presence of proteinuria, and small body mass.

1,458 citations


Journal ArticleDOI
TL;DR: Long-term intensified insulin treatment, as compared with standard treatment, retards the development of microvascular complications in patients with insulin-dependent diabetes mellitus.
Abstract: Background A cause-and-effect relation between blood glucose concentrations and microvascular complications in patients with insulin-dependent diabetes mellitus has not been established. Methods We randomly assigned 102 patients with insulin-dependent diabetes mellitus, nonproliferative retinopathy, normal serum creatinine concentrations, and unsatisfactory blood glucose control to intensified insulin treatment (48 patients) or standard insulin treatment (54 patients). We then evaluated them for microvascular complications after 18 months and 3, 5, and 7.5 years. Results Mean (±SD) glycosylated hemoglobin values were reduced from 9.5 ±1.3 percent to 7.1 ±0.7 percent in the group receiving intensified treatment and from 9.4 ±1.4 percent to 8.5 ±0.7 percent in the group receiving standard treatment (P = 0.001). In 12 of the patients receiving intensified treatment (27 percent of those included in the analysis) and 27 of those receiving standard treatment (52 percent), serious retinopathy requiring photocoag...

1,202 citations


Journal ArticleDOI
06 Dec 1986-The Lancet
TL;DR: 36 patients with insulin-dependent diabetes mellitus who had 'Albustix'-negative urine but raised urinary albumin excretion were randomly assigned to either remaining on conventional insulin treatment or continuous subcutaneous insulin infusion and followed up for 2 years.
Abstract: 36 patients with insulin-dependent diabetes mellitus who had 'Albustix'-negative urine but raised urinary albumin excretion (30 to 300 mg/24 h) were randomly assigned to either remaining on conventional insulin treatment or continuous subcutaneous insulin infusion and followed up for 2 years. The insulin-infusion group showed a significant, sustained improvement in metabolic control, with a median glycosylated haemoglobin of 7.2% (range 5.9-8.8), but there was no change in the conventional-treatment group (median 8.6%, range 7.2-13.4) (p less than 0.001). Clinical diabetic nephropathy (a urinary albumin excretion rate above 300 mg/24 h in at least two of three 24 h urine collections) developed in 5 patients in the conventional-treatment group, but not in the insulin-infusion group (p less than 0.05, two-tailed). Fractional albumin clearance (mean and range X 10(7] increased in the conventional-treatment group from 160 (35-468) to 360 (29-1580) and was unchanged in the insulin-infusion group (170 [31-608] before to 160 [26-460] after) (p less than 0.05). Insulin infusion had an overall beneficial effect on the annual increase in urinary albumin excretion (p less than 0.05), and the mean glycosylated haemoglobin values correlated positively with annual change in albumin excretion (r = 0.57, p less than 0.0001). The diastolic blood pressure rose significantly in the conventional-treatment group (p less than 0.001), and annual change in mean blood pressure correlated with change in urinary albumin excretion (r = 0.49, p less than 0.001).

452 citations


Journal ArticleDOI
Torsten Deckert1, Jacob E. Poulsen1, Larsen M1Institutions (1)
01 Jun 1978-Diabetologia
TL;DR: Clinical manifestations of late diabetic complications were considerably less common in patients who were still alive after more than forty years of diabetes than in Patients who died before their fortieth year of diabetes.
Abstract: In 307 patients with diabetes mellitus, developed prior to 1933 and before age 31 it was demonstrated that: (1) frequent contact with a specialized diabetes clinic from an early stage of the disease; (2) a good quality of “metabolic control”; (3) a low insulin dose; (4) a body weight of 10% less than ideal; and (5) a mean blood pressure below 100 mm Hg, all had significantly beneficial effects upon the survival. It was also found that patients domiciled in Copenhagen had a significantly better prognosis than patients domiciled outside Copenhagen. Frequent contact with a diabetes centre was accompanied by an appreciable decrease in disabling late diabetic complications.

444 citations