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      The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study

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          Abstract

          Objective To determine whether there is a link between hypoglycaemia and mortality among participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

          Design Retrospective epidemiological analysis of data from the ACCORD trial.

          Setting Diabetes clinics, research clinics, and primary care clinics.

          Participants Patients were eligible for the ACCORD study if they had type 2 diabetes, a glycated haemoglobin (haemoglobin A 1C) concentration of 7.5% or more during screening, and were aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of subclinical disease or two additional cardiovascular risk factors.

          Intervention Intensive (haemoglobin A 1C <6.0%) or standard (haemoglobin A 1C 7.0-7.9%) glucose control.

          Outcome measures Symptomatic, severe hypoglycaemia, manifest as either blood glucose concentration of less than 2.8 mmol/l (<50 mg/dl) or symptoms that resolved with treatment and that required either the assistance of another person or medical assistance, and all cause and cause specific mortality, including a specific assessment for involvement of hypoglycaemia.

          Results 10 194 of the 10 251 participants enrolled in the ACCORD study who had at least one assessment for hypoglycaemia during regular follow-up for vital status were included in this analysis. Unadjusted annual mortality among patients in the intensive glucose control arm was 2.8% in those who had one or more episodes of hypoglycaemia requiring any assistance compared with 1.2% for those with no episodes (53 deaths per 1924 person years and 201 deaths per 16 315 person years, respectively; adjusted hazard ratio (HR) 1.41, 95% CI 1.03 to 1.93). A similar pattern was seen among participants in the standard glucose control arm (3.7% (21 deaths per 564 person years) v 1.0% (176 deaths per 17 297 person years); adjusted HR 2.30, 95% CI 1.46 to 3.65). On the other hand, among participants with at least one hypoglycaemic episode requiring any assistance, a non-significantly lower risk of death was seen in those in the intensive arm compared with those in the standard arm (adjusted HR 0.74, 95% 0.46 to 1.23). A significantly lower risk was observed in the intensive arm compared with the standard arm in participants who had experienced at least one hypoglycaemic episode requiring medical assistance (adjusted HR 0.55, 95% CI 0.31 to 0.99). Of the 451 deaths that occurred in ACCORD up to the time when the intensive treatment arm was closed, one death was adjudicated as definitely related to hypoglycaemia.

          Conclusion Symptomatic, severe hypoglycaemia was associated with an increased risk of death within each study arm. However, among participants who experienced at least one episode of hypoglycaemia, the risk of death was lower in such participants in the intensive arm than in the standard arm. Symptomatic, severe hypoglycaemia does not appear to account for the difference in mortality between the two study arms up to the time when the ACCORD intensive glycaemia arm was discontinued.

          Trial registration NCT00000620.

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          Most cited references24

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          Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus.

          In persons with diabetes, chronic hyperglycemia (assessed by glycosylated hemoglobin level) is related to the development of microvascular disease; however, the relation of glycosylated hemoglobin to macrovascular disease is less clear. To conduct a meta-analysis of observational studies of the association between glycosylated hemoglobin and cardiovascular disease in diabetic persons. Search of the MEDLINE database by using Medical Subject Heading search terms and key words related to glycosylated hemoglobin, diabetes, and cardiovascular disease. Prospective cohort studies with data on glycosylated hemoglobin levels and incident cardiovascular disease. Relative risk estimates were derived or abstracted from each cohort study that met the inclusion criteria. Adjusted relative risk estimates for glycosylated hemoglobin (total glycosylated hemoglobin, hemoglobin A1, or hemoglobin A1c levels) and cardiovascular disease events (coronary heart disease and stroke) were pooled by using random-effects models. Three studies involved persons with type 1 diabetes (n = 1688), and 10 studies involved persons with type 2 diabetes (n = 7435). The pooled relative risk for cardiovascular disease was 1.18; this represented a 1-percentage point increase in glycosylated hemoglobin level (95% CI, 1.10 to 1.26) in persons with type 2 diabetes. Results in persons with type 1 diabetes were similar but had a wider CI (pooled relative risk, 1.15 [CI, 0.92 to 1.43]). This review largely reflects the limitations of the literature. Important concerns were residual confounding, the possibility of publication bias, the small number of studies, and the heterogeneity of study results. Pending confirmation from large, ongoing clinical trials, this analysis shows that observational studies are consistent with limited clinical trial data and suggests that chronic hyperglycemia is associated with an increased risk for cardiovascular disease in persons with diabetes.
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            Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials

            Diabetes is defined by its association with hyperglycemia-specific microvascular complications; however, it also imparts a two- to fourfold risk of cardiovascular disease (CVD). Although microvascular complications can lead to significant morbidity and premature mortality, by far the greatest cause of death in people with diabetes is CVD. Results from randomized controlled trials have demonstrated conclusively that the risk of microvascular complications can be reduced by intensive glycemic control in patients with type 1 (1,2) and type 2 diabetes (3–5). In the Diabetes Control and Complications Trial (DCCT), there was an ∼60% reduction in development or progression of diabetic retinopathy, nephropathy, and neuropathy between the intensively treated group (goal A1C 9%) to good control (e.g., A1C <7%). All three trials were carried out in participants with established diabetes (mean duration 8–11 years) and either known CVD or multiple risk factors, suggesting the presence of established atherosclerosis. Subset analyses of the three trials suggested a significant benefit of intensive glycemic control on CVD in participants with shorter duration of diabetes, lower A1C at entry, and/or or absence of known CVD. The finding of the DCCT follow-up study, that intensive glycemic control initiated in relatively young participants free of CVD risk factors was associated with a 57% reduction in major CVD outcomes, supports the above hypothesis. Of note, the benefit on CVD in the DCCT-EDIC (Epidemiology of Diabetes Interventions and Complications) required 9 years of follow-up beyond the end of the DCCT to become statistically significant. A recent report (13) of 10 years of follow-up of the UKPDS cohort describes, for the participants originally randomized to intensive glycemic control compared with those randomized to conventional glycemic control, long-term reductions in MI (15% with sulfonylurea or insulin as initial pharmacotherapy and 33% with metformin as initial pharmacotherapy, both statistically significant) and in all-cause mortality (13 and 27%, respectively, both statistically significant). These findings support the hypothesis that glycemic control early in the course of type 2 diabetes may have CVD benefit. As is the case with microvascular complications, it may be that glycemic control plays a greater role before macrovascular disease is well developed and a minimal or no role when it is advanced. People with type 1 diabetes, in whom insulin resistance does not predominate, tend to have lower rates of coexisting obesity, hypertension, and dyslipidemia than those with type 2 diabetes and yet are also at high lifetime risk of CVD (14). It is possible that CVD is more strongly glycemia mediated in type 1 diabetes and that intervening on glycemia would ameliorate CVD to a greater extent in type 1 than in type 2 diabetes. Finally, the inability of ACCORD, ADVANCE, and VADT to demonstrate significant reduction of CVD with intensive glycemic control could also suggest that current strategies for treating hyperglycemia in patients with more advanced type 2 diabetes may have counter-balancing consequences for CVD (such as hypoglycemia, weight gain, or other metabolic changes). Results of long-term CVD outcome trials utilizing specific antihyperglycemic drugs, intensive lifestyle therapy (such as the Look AHEAD [Action for Health in Diabetes] study), bariatric surgery, or other emerging therapies may shed light on this issue. 4. What are the implications of these findings for clinical care? The benefits of intensive glycemic control on microvascular and neuropathic complications are well established for both type 1 and type 2 diabetes. The ADVANCE trial has added to that evidence base by demonstrating a significant reduction in the risk of new or worsening albuminuria when median A1C was lowered to 6.3% compared with standard glycemic control achieving an A1C of 7.0%. The lack of significant reduction in CVD events with intensive glycemic control in ACCORD, ADVANCE, and VADT should not lead clinicians to abandon the general target of an A1C <7.0% and thereby discount the benefit of good control on serious and debilitating microvascular complications. The ADA's Standards of Medical Care in Diabetes (6) and the AHA and ADA's scientific statement on prevention (15) advocate controlling nonglycemic risk factors (through blood pressure control, lipid lowering with statin therapy, aspirin therapy, and lifestyle modifications) as the primary strategies for reducing the burden of CVD in people with diabetes. The lower-than-predicted CVD rates in ACCORD, ADVANCE, and VADT, as well as the recent long-term follow-up of the Steno-2 multiple risk factor intervention (16), provide strong confirmation of the concept that comprehensive care for diabetes involves treatment of all vascular risk factors—not just hyperglycemia. The evidence for a cardiovascular benefit of intensive glycemic control remains strongest for those with type 1 diabetes. However, subset analyses of ACCORD, ADVANCE, and VADT suggest the hypothesis that patients with shorter duration of type 2 diabetes and without established atherosclerosis might reap cardiovascular benefit from intensive glycemic control. Conversely, it is possible that potential risks of intensive glycemic control may outweigh its benefits in other patients, such as those with a very long duration of diabetes, known history of severe hypoglycemia, advanced atherosclerosis, and advanced age/frailty. Certainly, providers should be vigilant in preventing severe hypoglycemia in patients with advanced disease and should not aggressively attempt to achieve near-normal A1C levels in patients in whom such a target cannot be reasonably easily and safely achieved. The evidence obtained from ACCORD, ADVANCE, and VADT does not suggest the need for major changes in glycemic control targets but, rather, additional clarification of the language that has consistently stressed individualization: Microvascular disease: Lowering A1C to below or around 7% has been shown to reduce microvascular and neuropathic complications of type 1 and type 2 diabetes. Therefore, the A1C goal for nonpregnant adults in general is <7%. ADA, A-level recommendation; ACC/AHA, class I recommendation (level of evidence A). Macrovascular disease: In type 1 and type 2 diabetes, randomized controlled trials of intensive versus standard glycemic control have not shown a significant reduction in CVD outcomes during the randomized portion of the trials. However, long-term follow-up of the DCCT and UKPDS cohorts suggests that treatment to A1C targets below or around 7% in the years soon after the diagnosis of diabetes is associated with long-term reduction in risk of macrovascular disease. Until more evidence becomes available, the general goal of <7% appears reasonable. ADA, B-level recommendation; ACC/AHA, class IIb recommendation (level of evidence A). For some patients, individualized glycemic targets other than the above general goal may be appropriate: Subgroup analyses of clinical trials such as the DCCT and UKPDS and the microvascular evidence from the ADVANCE trial suggest a small but incremental benefit in microvascular outcomes with A1C values closer to normal. Therefore, for selected individual patients, providers might reasonably suggest even lower A1C goals than the general goal of <7% if this can be achieved without significant hypoglycemia or other adverse effects of treatment. Such patients might include those with short duration of diabetes, long life expectancy, and no significant cardiovascular disease. ADA, B-level recommendation; ACC/AHA, class IIa recommendation (level of evidence C). Conversely, less stringent A1C goals than the general goal of <7% may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, or extensive comorbid conditions or those with long-standing diabetes in whom the general goal is difficult to attain despite diabetes self-management education, appropriate glucose monitoring, and effective doses of multiple glucose-lowering agents including insulin. ADA, C-level recommendation; ACC/AHA, class IIa recommendation (level of evidence C). For primary and secondary CVD risk reduction in patients with diabetes, providers should continue to follow the evidence-based recommendations for blood pressure treatment, including lipid-lowering with statins, aspirin prophylaxis, smoking cessation, and healthy lifestyle behaviors delineated in the ADA Standards of Medical Care in Diabetes (6) and the AHA/ADA guidelines for primary CVD prevention (15).
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              Association of hypoglycemia and cardiac ischemia: a study based on continuous monitoring.

              In some studies intensive diabetes treatment in patients with type 2 diabetes may be associated with increased cardiovascular events. It is not clear whether these events are related to hypoglycemic episodes. To determine whether episodes of hypoglycemia were more likely to be associated with cardiac ischemia than normoglycemia or hyperglycemia, we carried out a study in 21 patients with coronary artery disease (CAD) and type 2 diabetes treated with insulin who had good glycemic control. We carried out 72-h continuous glucose monitoring along with simultaneous cardiac Holter monitoring for ischemia. Patients also recorded symptoms of cardiac ischemia (chest pain) and symptoms of hypoglycemia. Satisfactory continuous glucose monitoring system recordings were obtained in 19 patients. We recorded 54 episodes of hypoglycemia (blood glucose 200 mg/dl; none symptomatic). Of the 54 episodes of hypoglycemia, 10 were associated with symptoms of chest pain, during 4 of which electrocardiographic abnormalities were documented. In contrast, only 1 episode of chest pain occurred during 59 episodes of hyperglycemia. No chest pain or electrocardiographic abnormalities occurred when the blood glucose was within the normal range. The difference between the frequency of ischemia during hypoglycemia and the frequency during both hyperglycemia and normoglycemia was statistically significant (P 100 mg over a 60-min period, and ischemic symptoms occurred during 9 of these episodes (P < 0.01 compared with stable normoglycemia or hyperglycemia). Hypoglycemia is more likely to be associated with cardiac ischemia and symptoms than normoglycemia and hyperglycemia, and it is particularly common in patients who experience considerable swings in blood glucose. These data may be important in the institution of insulin treatment and attempting near-normal glycemia in patients with known CAD. Further research is needed to determine strategies to prevent ischemia associated with hypoglycemia.
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                Author and article information

                Contributors
                Role: medical officer
                Role: professor of biostatistics
                Role: executive director
                Role: professor of medicine
                Role: professor of epidemiology and prevention
                Role: research consultant
                Role: diabetes clinical lead
                Role: professor of medicine
                Role: research associate
                Role: clinical research physician
                Role: associate professor of medicine
                Role: senior advisor for clinical diabetes studies
                Role: professor of medicine
                Role: associate professor of medicine
                Role: professor of medicine
                Role: senior clinical investigator
                Role: associate professor of medicine
                Journal
                BMJ
                bmj
                BMJ : British Medical Journal
                BMJ Publishing Group Ltd.
                0959-8138
                1468-5833
                2010
                2010
                08 January 2010
                : 340
                : b4909
                Affiliations
                [1 ]National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
                [2 ]Division of Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, NC 27157-1063, USA
                [3 ]International Diabetes Center at Park Nicollet, Minneapolis, MN 55416-2699, USA
                [4 ]University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA
                [5 ]Care Management Institute, Kaiser Permanente, Oakland, CA 94612, USA
                [6 ]Case Western Reserve University, Cleveland, OH 44106, USA
                [7 ]Department of Endocrinology, Diabetes, and Metabolism, Cleveland Clinic, Cleveland, OH 44195, USA
                [8 ]Lilly USA, Lilly Corporate Center, Indianapolis, IN 46285, USA
                [9 ]National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD 20892, USA
                [10 ]Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
                [11 ]University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
                [12 ]John L McClellan Memorial Veterans Hospital, Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA
                [13 ]Department of Internal Medicine, University of Iowa Health Care, Iowa City, IA 52242, USA
                [14 ]HealthPartners Research Foundation, Minneapolis, MN 55440-1524, USA
                [15 ]Emory University School of Medicine, Atlanta, GA 30322, USA
                [16 ]Atlanta Veterans Administration Medical Center, Atlanta, GA 30033, USA
                Author notes
                Correspondence to: DE Bonds bondsde@ 123456nhlbi.nih.gov
                Article
                bond682633
                10.1136/bmj.b4909
                2803744
                20061358
                464fbe82-52f1-4fdb-a895-be5d77c25375
                © Bonds et al 2010

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

                History
                : 30 September 2009
                Categories
                Research
                Epidemiologic studies
                General practice / family medicine
                Drugs: cardiovascular system
                Screening (epidemiology)
                Diabetes
                Metabolic disorders
                Screening (public health)

                Medicine
                Medicine

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