严重低血糖与临床不良事件预后的相关性

original article T h e n e w e ngl a nd j o u r na l o f m e dic i n e n engl j med 363;15 nejm.org october 7, 20101410 Severe Hypoglycemia and Risks of Vascular Events and Death Sophia Zoungas, M.D., Ph.D., Anushka Patel, M.D., Ph.D., John Chalmers, M.D., Ph.D., Bastiaan E. de Galan, M.D., Ph.D., Qiang Li, M.Biostat., Laurent Billot, M.Sc., Mark Woodward, Ph.D., Toshiharu Ninomiya, M.D., Ph.D., Bruce Neal, M.D., Ph.D., Stephen MacMahon, D.Sc., Ph.D., Diederick E. Grobbee, M.D., Ph.D., Andre Pascal Kengne, M.D., Ph.D., Michel Marre, M.D., Ph.D., and Simon Heller, M.D., for the ADVANCE Collaborative Group From the George Institute for Interna­ tional Health, University of Sydney, Syd­ ney (S.Z., A.P., J.C., B.E.G., Q.L.M., L.B., M.W., T.N., B.N., S.M., A.P.K.); the School of Public Health, Monash University, Mel­ bourne, Australia (S.Z.); the Department of General Internal Medicine, Radboud University Nijmegen Medical Center, Nij­ megen (B.E.G.), and the Julius Center for Health Sciences and Primary Care, Uni­ versity Medical Center Utrecht, Utrecht (D.E.G.) — both in the Netherlands; Mount Sinai School of Medicine, New York (M.W.); Hôpital Bichat–Claude Ber­ nard and Université Paris, Paris (M.M.); and the University of Sheffield and Shef­ field Teaching Hospitals National Health Service Foundation Trust, Sheffield, United Kingdom (S.H.). Address reprint requests to Dr. Zoungas at the George Institute for International Health, University of Sydney, P.O. Box M201, Missenden Rd., Sydney, NSW 2050, Australia, or at szoungas@ george.org.au. N Engl J Med 2010;363:1410­8. Copyright © 2010 Massachusetts Medical Society. A bs tr ac t Background Severe hypoglycemia may increase the risk of a poor outcome in patients with type 2 diabetes assigned to an intensive glucose-lowering intervention. We analyzed data from a large study of intensive glucose lowering to explore the relationship between severe hypoglycemia and adverse clinical outcomes. Methods We examined the associations between severe hypoglycemia and the risks of mac- rovascular or microvascular events and death among 11,140 patients with type 2 dia- betes, using Cox proportional-hazards models with adjustment for covariates mea- sured at baseline and after randomization. Results During a median follow-up period of 5 years, 231 patients (2.1%) had at least one severe hypoglycemic episode; 150 had been assigned to intensive glucose control (2.7% of the 5571 patients in that group), and 81 had been assigned to standard glucose control (1.5% of the 5569 patients in that group). The median times from the onset of severe hypoglycemia to the first major macrovascular event, the first major mi- crovascular event, and death were 1.56 years (interquartile range, 0.84 to 2.41), 0.99 years (interquartile range, 0.40 to 2.17), and 1.05 years (interquartile range, 0.34 to 2.41), respectively. During follow-up, severe hypoglycemia was associated with a sig- nificant increase in the adjusted risks of major macrovascular events (hazard ratio, 2.88; 95% confidence interval [CI], 2.01 to 4.12), major microvascular events (hazard ratio, 1.81; 95% CI, 1.19 to 2.74), death from a cardiovascular cause (hazard ratio, 2.68; 95% CI, 1.72 to 4.19), and death from any cause (hazard ratio, 2.69; 95% CI, 1.97 to 3.67) (P<0.001 for all comparisons). Similar associations were apparent for a range of nonvascular outcomes, including respiratory, digestive, and skin conditions (P<0.01 for all comparisons). No relationship was found between repeated episodes of severe hypoglycemia and vascular outcomes or death. Conclusions Severe hypoglycemia was strongly associated with increased risks of a range of ad- verse clinical outcomes. It is possible that severe hypoglycemia contributes to adverse outcomes, but these analyses indicate that hypoglycemia is just as likely to be a marker of vulnerability to such events. (Funded by Servier and the National Health and Medical Research Council of Australia; ClinicalTrials.gov number, NCT00145925.) The New England Journal of Medicine Downloaded from www.nejm.org at UC SHARED JOURNAL COLLECTION on October 8, 2010. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved. Severe Hypoglycemia and Risks of Vascular Events and Death n engl j med 363;15 nejm.org october 7, 2010 1411 In patients with diabetes treated with insulin or insulin secretagogues, severe hypo-glycemia is more common when glucose con- trol is intensified.1-4 Although most episodes of severe hypoglycemia resolve without apparent per- manent injury, there are anecdotal reports of acute coronary syndromes coinciding with hypoglyce- mia in people with type 2 diabetes.5,6 In addition, observational studies have suggested that hypo- glycemia and reduced levels of glycated hemo- globin are associated with an increased risk of death in patients with diabetes or hyperglyce- mia who have been hospitalized for myocardial infarction.7-11 Recently completed trials investigating the ef- fect of intensive glucose control on macrovascular outcomes in patients with long-standing type 2 diabetes have individually failed to demonstrate clear reductions in cardiovascular events or mor- tality.1-3 A meta-analysis showed that intensive glucose control reduced the risk of myocardial infarction by 15%, with no adverse effect on the risk of death, but that it simultaneously increased the risk of severe hypoglycemia.12 Nonetheless, the excess mortality observed with intensive glu- cose control in the Action to Control Cardiovas- cular Risk in Diabetes (ACCORD) study has fueled speculation about the adverse effects of such regi- mens in patients with type 2 diabetes.13 Post hoc analyses of ACCORD study data suggest that the excess mortality in the intensively treated group was not directly explained by the high rate of hy- poglycemia.14 We examined the relationship between severe hypoglycemia and the subsequent risks of vascu- lar complications and death among 11,140 pa- tients with type 2 diabetes who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Eval- uation (ADVANCE) study (ClinicalTrials.gov num- ber, NCT00145925). Me thods Study Design and Oversight ADVANCE was a factorial trial with two random- ized comparisons: a double-blind assessment of the efficacy of perindopril–indapamide in lower- ing blood pressure, as compared with placebo, and an open-label assessment of the effects of inten- sive glucose lowering with the use of a modified- release formulation of gliclazide as compared with standard, guideline-based glucose lowering on the risks of vascular outcomes and death among pa- tients with type 2 diabetes. Approval for the trial was obtained from the ethics committee of each study center, and all participants provided written informed consent.3,15 The main results for each comparison have been reported previously.3,15 Study Population A total of 11,140 patients who were at least 55 years of age were recruited for the study from 215 cen- ters in 20 countries between June 2001 and March 2003. Eligible patients had received a diagnosis of type 2 diabetes after the age of 30 years and had a history of major macrovascular or microvascu- lar disease or at least one other cardiovascular risk factor.3 No threshold for level of blood glu- cose or glycated hemoglobin was specified for in- clusion in the study, although patients with a clear indication for long-term insulin use at baseline were ineligible. Patients assigned to the intensive glucose-lowering intervention were given modi- fied-release gliclazide (Diamicron MR, Servier) and other glucose-lowering drugs as required, with a target glycated hemoglobin level of 6.5% or less.3 Weight, height, blood pressure, and levels of gly- cated hemoglobin and serum creatinine were mea- sured at baseline, at 4 months, and every 6 months thereafter.3 Definition of Hypoglycemia Hypoglycemia was defined as a blood glucose level of less than 2.8 mmol per liter (50 mg per decili- ter) or the presence of typical symptoms and signs of hypoglycemia without other apparent cause. Patients with transient dysfunction of the central nervous system who were unable to treat them- selves (requiring help from another person) were considered to have severe hypoglycemia. Episodes of severe hypoglycemia were reported at the time of their occurrence during study follow-up, with a full description of the event. Each report was reviewed to confirm that the criteria were met. Patients with transient dysfunction of the central nervous system who were able to treat themselves were considered to have minor hypoglycemia. Episodes of minor hypoglycemia were reported at follow-up visits. Clinical Outcomes The primary clinical outcomes considered were the first major macrovascular event (death from a cardiovascular cause, nonfatal myocardial infarc- tion, or nonfatal stroke) and the first major micro- The New England Journal of Medicine Downloaded from www.nejm.org at UC SHARED JOURNAL COLLECTION on October 8, 2010. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved. T h e n e w e ngl a nd j o u r na l o f m e dic i n e n engl j med 363;15 nejm.org october 7, 20101412 vascular event (new or worsening nephropathy or retinopathy). The secondary outcomes considered were death from any cause and death from a car- diovascular event. Primary and secondary out- comes were validated by an independent adjudi- cation committee whose members were unaware of the treatment assignments.3 Nonvascular clin- ical outcomes were reported during follow-up as serious adverse events and coded according to the International Classification of Diseases, 9th Revision. Statistical Analysis A full description of the statistical analysis is pro- vided in the Supplementary Appendix, available with the full text of this article at NEJM.org. In brief, rates of severe and minor hypoglycemia dur- ing follow-up were estimated for the entire cohort and according to treatment assignments. Baseline risk factors for severe hypoglycemia were exam- ined with the use of univariate and multivariate- adjusted Cox proportional regression models. In- cidence rates of clinical outcomes according to hypoglycemic status were examined in the entire cohort. Crude, annualized mortality rates within each glucose treatment group (intensive glucose control and standard glucose control) for patients who did and those who did not report severe hypo- glycemia were determined by dividing the num- ber of deaths by the cumulative time at risk. Associations between severe hypoglycemia and clinical outcomes were tested with the use of time- dependent Cox proportional-hazards models of the time from randomization to the first clinical outcome. Models were adjusted for all baseline and time-dependent covariates (variables measured during follow-up) that were thought to be poten- tial confounders, as listed in the Supplementary Appendix. For each clinical outcome, the follow- up time for every patient was divided into as many intervals as there were distinct event times in the whole cohort. Each interval included the latest measured value for each time-dependent covariate and a variable indicating whether the patient had the clinical outcome of interest during that inter- val.16 Follow-up for each participant was consid- ered separately for each major outcome and ended on the date of the first clinical event, the date of death, or the date of data censoring at study completion. The primary analysis assumed that patients were exposed to hypoglycemia from the time of the first severe hypoglycemic episode until the end of follow-up or the occurrence of a clinical event. Additional sensitivity analyses tested various expo- sure times, use of logistic-regression models, and additional adjustment for cardiovascular events occurring after randomization, as described in the Supplementary Appendix. Model predictive capac- ity, with and without severe hypoglycemia, was tested with the use of C statistics,17 the integrated- discrimination-improvement statistic,18 and the Hosmer–Lemeshow chi-square statistic.19 Analy- ses were performed with the use of SAS statisti- cal software, version 9.1 (SAS Institute). All statis- tical tests were two-sided, and a P value of less than 0.05 was considered to indicate statistical significance, but all results were interpreted in light of the many comparisons made. R esult s Rates of Hypoglycemia over Time During a median follow-up period of 5 years, 231 of 11,140 study patients (2.1%) reported 299 se- vere hypoglycemic events: 150 patients in the in- tensive-intervention group (2.7%) reported 195 events, and 81 patients in the standard-interven- tion group (1.5%) reported 104 events (Table 1). Over time, the rate of severe hypoglycemia in- creased in the group undergoing intensive glucose control (P<0.001 for trend) but remained relatively stable in the group receiving standard treatment (P = 0.38 for trend) (Fig. 1A). A total of 4975 pa- tients (44.7%) reported minor hypoglycemia dur- ing follow-up; 2898 of these patients (52.0%) had been assigned to intensive control and 2077 (37.3%) to standard control (Table 1). Risk Factors for Severe Hypoglycemia Univariate and multivariate analyses showed that the following variables were independent risk fac- tors for severe hypoglycemia: older age, longer du- ration of diabetes, higher creatinine levels, lower body-mass index, lower cognitive function, use of two or more oral glucose-lowering drugs, history of smoking or microvascular disease, and assign- ment to intensive glucose control (P<0.05 for all comparisons; for details, see Table 1 in the Sup- plementary Appendix). When these analyses were stratified according to treatment group, the risk factors for severe hypoglycemia were similar. Association of Severe Hypoglycemia with Vascular Outcomes and Death During follow-up, 2125 patients had a major mac- rovascular or microvascular event, 87 of whom re- The New England Journal of Medicine Downloaded from www.nejm.org at UC SHARED JOURNAL COLLECTION on October 8, 2010. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved. Severe Hypoglycemia and Risks of Vascular Events and Death n engl j med 363;15 nejm.org october 7, 2010 1413 ported severe hypoglycemia (before the event in 40 patients and after the event in 47), and 1031 patients died, 45 of whom had reported severe hy- poglycemia. The median times from the episode of severe hypoglycemia to the subsequent first major macrovascular or microvascular event were 1.56 years (interquartile range, 0.84 to 2.41) and 0.99 years (interquartile range, 0.40 to 2.17), re- spectively. The median time from severe hypogly- cemia to death was 1.05 years (interquartile range, 0.34 to 2.41) — 1.31 years (interquartile range, 0.80 to 2.41) for death from a cardiovascular event and 0.74 years (interquartile range, 0.13 to 2.60) for death from a noncardiovascular cause (Fig. 1B). Among patients who reported severe hypogly- cemia, 16.8% (35 of 208) had a subsequent major macrovascular event, 11.5% (24 of 209) had a sub- sequent major microvascular event, and 19.5% (45 of 231) died; the respective rates for those who did not report severe hypoglycemia were 10.2% (1112 of 10,932 patients), 10.1% (1107 of 10,931), and 9.0% (986 of 10,909), respectively. The propor- tions of patients who died from cardiovascular causes and from noncardiovascular causes were similar among patients reporting severe hypogly- cemia (49% and 51%, respectively) and those not reporting severe hypoglycemia (53% and 47%, re- spectively; P = 0.09). For those reporting severe hy- poglycemia, annual death rates were lower in the group receiving intensive treatment than in the group receiving standard treatment (3.6% vs. 5.1%). In contrast, for those not reporting severe hypo- glycemia, annual death rates were similar in the two treatment groups (1.8% with the intensive intervention and 1.9% with standard treatment) (Table 2). There was no evidence of interaction among severe hypoglycemia, the assigned glucose- lowering treatment, and the risk of death (P = 0.30). The unadjusted risks of a major macrovascular event, a major microvascular event, death from any cause, and death from a cardiovascular or non- cardiovascular cause were significantly increased among patients who had severe hypoglycemia as compared with those who did not (Table 3). After adjustment for a number of potential confound- ing variables measured at baseline or during fol- low-up, the associations were markedly attenuated but remained significant (P<0.01 for all com- parisons). In analyses in which the period of follow-up after a severe hypoglycemic episode was limited to 3 months and to 6 months, the unadjusted and adjusted associations with all major macrovascu- lar outcomes and death (from any cause or from a cardiovascular or noncardiovascular cause), re- mained significant (Table 3). The adjusted asso- ciations for major microvascular events were no longer significant when the period was limited to 3 months, but the point estimates of association were similar (Table 3). When the analyses were Table 1. Episodes of Severe and Minor Hypoglycemia in All Study Participants and According to Treatment Group. Variable All Participants (N = 11,140) Intensive Glucose Control (N = 5571) Standard Glucose Control (N = 5569) Hazard Ratio (95% CI) Severe hypoglycemia 1.86 (1.40–2.40) No. of patients (%) 231 (2.1) 150 (2.7) 81 (1.5 ) No. of episodes One 184 120 64 Two 35 22 13 Three or more 12 8 4 Rate (per person per year) 0.006 0.007 0.004 Minor hypoglycemia 1.58 (1.49–1.68) No. of patients (%) 4975 (44.7) 2898 (52.0) 2077 (37.3) No. of episodes One 2610 1529 1081 Two 671 397 274 Three or more 1694 972 722 Rate (per person per year) 1.1 1.2 0.9 The New England Journal of Medicine Downloaded from www.nejm.org at UC SHARED JOURNAL COLLECTION on October 8, 2010. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved. T h e n e w e ngl a nd j o u r na l o f m e dic i n e n engl j med 363;15 nejm.org october 7, 20101414 stratified according to treatment group, the find- ings were consistent in the two groups (P>0.10 for all interactions). The observed associations were also similar among patients with and those without a history of macrovascular disease at study entry (P>0.10 for all interactions). There was no evidence of a dose–response re- lationship between repeated episodes of severe hypoglycemia and vascular outcomes or death, although few patients had recurrent events (for details, see Table 2 in the Supplementary Appen- dix). For example, the adjusted odds ratio for death from any cause was 1.57 (95% confidence interval [CI], 1.02 to 2.41) with a single severe hypoglyce- mic episode and 1.24 (95% CI, 0.58 to 2.68) with two or more episodes (P>0.10 for the comparison of risk among those reporting two or more hypo- glycemic episodes vs. those reporting one episode). When we examined the effect of adding the oc- currence of severe hypoglycemia to models pre- dicting absolute risks of vascular outcomes and death, we found no improvement in prediction for any outcome (P≥0.05 for all C statistics; for details, see Table 3 in the Supplementary Appendix). Association of Minor Hypoglycemia with Vascular Outcomes and Death The risks of major macrovascular outcom