Pengambilan Lebih Dari Satu Jenis Ubat Kencing Manis Atau Diabetes Mendatangkan Kesan Yang Tidak Baik

Abstract

METHODS

RESULTS

Baseline characteristics of the participants have been reported previously.⁶ Table 1 shows these characteristics before the transition date and at the final visit. Figure 1 in the Supplementary Appendix (available at NEJM.org) shows the completeness of follow-up in the two study groups. Median glycated hemoglobin levels before the transition date in the intensive-therapy and standard-therapy groups were 6.4% and 7.5%, respectively. After the transition date, therapy was relaxed (i.e., fewer drugs or lower doses were used) for a particular indication at least as often in the intensive-therapy group as in the standard-therapy group. For example, at the first post-transition visit, relaxation of therapy was indicated in 94% of participants in the intensive-therapy group and 69% of those in the standard-therapy group. At the final visit, median glycated hemoglobin levels were 7.2% in the intensive-therapy group and 7.6% in the standard-therapy group (Fig. 2 in the Supplementary Appendix). By the final visit, the numbers of participants who were receiving metformin, secretagogues, thiazolidinediones, insulin, and combination therapy with insulin and oral agents were similar in the two groups (Table 1 in the Supplementary Appendix). Rates of severe hypoglycemia and other adverse events within the two groups were similar after the transition (Table 2 in the Supplementary Appendix).

Figure 1 shows the incidence of the primary outcome and death from any cause from randomization until the time of transition, from randomization until the end of the whole study, and from the transition date until the termination of the trial. Figure 2 shows the effect of intensive glucose-lowering therapy on all the major outcomes, from randomization until the end of the active treatment period and until the end of the study. Before the transition, the incidence of the primary outcome among the participants in the intensive-therapy group was 2.0% per year, as compared with an incidence of 2.2% per year among the participants in the standard-therapy group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.03; nominal P = 0.132, and P = 0.134 after adjustment for repeat testing by the data and safety monitoring board) and remained nonsignificant throughout the entire period of observation (hazard ratio, 0.91; 95% CI, 0.81 to 1.03; P = 0.12).

The intensive therapy had different effects on two of the key components of this primary outcome. At the time of the transition, the rate of nonfatal myocardial infarction in the intensive-therapy group was lower than that in the standard-therapy group (1.08% vs. 1.35%; hazard ratio, 0.79; 95% CI, 0.66 to 0.95; P = 0.01), but the rate of death from cardiovascular causes was non-significantly higher (0.71% vs. 0.55%; hazard ratio, 1.27%; 95% CI, 0.99 to 1.63; P = 0.07). These divergent effects were retained at the end of the study, with a rate of nonfatal myocardial infarction in the intensive-therapy group that was lower than that in the standard-therapy group (1.18 vs. 1.42; hazard ratio, 0.82; 95% CI, 0.70 to 0.96; P = 0.01) and a rate of death from cardiovascular causes that was higher (0.74 vs. 0.57; hazard ratio, 1.29; 95% CI, 1.04 to 1.60; P = 0.02).

Finally, at the time of the transition, there was a 21% higher rate of death from any cause in the intensive-therapy group than in the standard-therapy group (1.42 vs. 1.16; 95% CI, 1.02 to 1.44; nominal P = 0.030 and P = 0.036 after adjustment for repeat testing by the data and safety monitoring board) and a 19% higher rate at the end of the study (1.53 vs. 1.27; 95% CI, 1.03 to 1.38; P = 0.02) (Fig. 1 and and2).2). The causes of death are listed in Table 2. There was no clear difference between study groups in any other predefined cardiovascular outcomes.

Table 3 lists the annual incidence of the primary and secondary outcomes in the two treatment groups after the transition date, and Figures 1C and 1F show the corresponding Kaplan–Meier curves for the primary outcome and death from any cause. Hazard ratios in the post-transition period were not significantly different from those in the pretransition period for either the primary outcome (ratio of pretransition to post-transition hazard ratios, 0.95; 95% CI, 0.72 to 1.26; P = 0.72) or death from any cause (ratio of pretransition to post-transition hazard ratios, 1.06; 95% CI, 0.76 to 1.46; P = 0.74). There was a possible difference in the effect of the intensive therapy on the pretransition primary outcome among participants with a baseline glycated hemoglobin level of 8% or less as compared with those with a level of more than 8% (P = 0.03 for interaction) (Fig. 3 in the Supplementary Appendix).

A total of 4733 participants were randomly assigned to receive either intensive or standard therapy to lower their blood pressure, and 5518 participants were randomly assigned to a statin plus either fenofibrate or placebo for control of low-density lipoprotein cholesterol. No significant interactions were noted between the glucose-lowering study and the blood-pressure study for the primary outcome, or between the glucose-lowering study and the lipid study for either the primary outcome or death from any cause. However, there was evidence of an interaction between the intensive glucose-lowering group and the intensive blood-pressure–lowering group with respect to death from any cause both before the transition (P = 0.03 for interaction) and at the end of the trial (P = 0.05 for interaction) (Fig. 4 in the Supplementary Appendix). Before the transition, this interaction was characterized by a marginally higher mortality rate in the intensive glucose-lowering group than in the standard glucose-lowering group among participants also assigned to the intensive blood-pressure–lowering group (hazard ratio, 1.45; 95% CI, 1.00 to 2.12; P = 0.05) but not among those also assigned to the standard blood-pressure–lowering group (hazard ratio, 0.78; 95% CI, 0.52 to 1.18; P = 0.24).

DISCUSSION

The ACCORD trial involved persons who had had diabetes for a median of 10 years, with a glycated hemoglobin level of at least 7.5%, and who had a high risk of cardiovascular disease. Our findings indicate that in a high-risk population such as this, a mean of 3.7 years of intensive therapy consisting of multiple glucose-lowering methods to target normal glycated hemoglobin levels (i.e., below 6.0%) does not result in a significantly lower number of major cardiovascular events after 5 years than does an approach that uses similar methods to target levels that are more typically achieved in persons in the United States and Canada (i.e., 7 to 7.9%). Indeed, the intensive approach led to more deaths. Effects on the primary outcome were similar during the 3.7-year glucose-lowering period and the entire 5-year follow-up period; effects on mortality also were similar during the two periods. Similar effects on the primary outcome and mortality were noted in most of the predefined subgroups. The nominally positive tests for interaction with respect to the primary outcome and baseline glycated hemoglobin levels and with respect to death from any cause and the blood-pressure intervention may well have been due to chance, since a large number of statistical tests were performed. No inferences can be made about the effect of the intervention during the post-transition period, because between-group differences during this period alone are likely to have been driven by between-group differences in the characteristics of participants who survived and were followed during this period.

Reasons for the higher mortality in the intensive-therapy group during the pretransition period remain unclear. Because of the equivalent rates of hypoglycemia in the post-transition period, severe hypoglycemia cannot be implicated. Additional analyses reported elsewhere¹² also do not implicate severe hypoglycemia. According to other analyses, the degree of reduction in glycated hemoglobin levels cannot be implicated.¹¹ Further analyses should explore possible explanations, such as the role of various drugs, drug combinations, or drug interactions; weight gain; the relatively short intervention period (3.7 years); and the observed interaction between the blood-pressure and glycemia trials with respect to mortality.

Strengths of our study include the randomized trial design, large sample, wide variety of clinics, frequent follow-up, high rate of complete follow-up, high rate of adherence to the study assignment, and adjudication of all events by a central committee that was unaware of the study-group assignments. The clinical relevance of the results is highlighted by the following facts: the approach used commonly available drugs, glycemia was managed within the context of good control of blood pressure and lipid levels, the recruited participants were representative of many people with diabetes who are currently receiving care in ambulatory settings, and several organizations have recommended glycemic targets of 6.5% or lower.

These findings are most applicable to middle-aged and older patients with a long duration of diabetes, a high risk of cardiovascular disease, and hyperglycemia and should be interpreted in light of the specific features of the ACCORD trial. For example, the ACCORD trial excluded people with glycated hemoglobin levels below 7.5%. Moderate heterogeneity with respect to subgroups predefined by the glycated hemoglobin level at baseline (Fig. 3 in the Supplementary Appendix) suggests that participants whose glycated hemoglobin level at baseline was 8% or lower may have had a better response to therapy than participants with higher glycated hemoglobin levels. Although this hypothesis is clearly not proved by the ACCORD trial, it is supported by a recent epidemiologic analysis of the cardiovascular effect of glucose lowering in a cohort of people with type 2 diabetes.¹⁴

The ACCORD trial explicitly tested whether targeting a glycated hemoglobin level below 6% by means of a large menu of glucose-lowering agents is superior to targeting a glycated hemoglobin level of 7 to 7.9%. Therefore, our findings should be interpreted in relation to these therapies and target glycated hemoglobin levels. Furthermore, targeting normal glycated hemoglobin levels (i.e., <6.0%) required the use of multiple combinations of glucose-lowering medications in ways that are not used in standard care. For example, 42% of participants in the intensive-therapy group were receiving three or more classes of oral agents, either alone (17%) or in combination with insulin (25%), whereas such combinations were used in 19% of the participants in the standard-therapy group (Table 1 in the Supplementary Appendix). Whether these unconventional combinations were responsible for the results and whether similar findings would have been observed with newer glucose-lowering therapies, different drug combinations, or different target glycated hemoglobin levels is unknown.

Finally, people with newly diagnosed diabetes may have a different response to intensive glucose-lowering therapy. A large trial involving people with newly diagnosed type 2 diabetes, in which normal glucose levels were targeted and a median glycated hemoglobin level of 7% (as opposed to 7.9%) was achieved, showed a neutral cardiovascular effect after 10 years but a reduced rate of myocardial infarction and death after 20 years.¹⁵

In summary, the results of the ACCORD trial show that in persons who have a high risk of cardiovascular disease and suboptimally controlled, long-standing diabetes, with good blood-pressure and lipid control, an intensive therapeutic approach targeting normal glycated hemoglobin levels with the use of multiple medications is associated with higher mortality than is a standard approach targeting higher glycated hemoglobin levels. The higher risk of death from any cause and from cardiovascular causes in the intensive-therapy group means that a therapeutic approach that targets glycated hemoglobin levels below 6% cannot be generally recommended in this population. Thus, the results of the ACCORD trial suggest a lower limit for glycemic targets, achieved with the use of multiple combinations of currently available approaches.

Supplementary Material

Acknowledgments

Appendix

The members of the writing group (Hertzel C. Gerstein, M.D., McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada; Michael E. Miller, Ph.D., Wake Forest University School of Medicine, Winston-Salem, NC; Saul Genuth, M.D., Case Western Reserve University, Cleveland; Faramarz Ismail-Beigi, M.D., Ph.D., Case Western Reserve University, Cleveland; John B. Buse, M.D., Ph.D., University of North Carolina, Chapel Hill; David C. Goff, Jr., M.D., Ph.D., Wake Forest University School of Medicine, Winston-Salem, NC; Jeffrey L. Probstfield, M.D., University of Washington, Seattle; William C. Cushman, M.D., Memphis Veterans Affairs Medical Center, Memphis; Henry N. Ginsberg, M.D., Columbia University College of Physicians and Surgeons, New York; J. Thomas Bigger, M.D., Columbia University College of Physicians and Surgeons, New York; Richard H. Grimm, Jr., M.D., Ph.D, University of Minnesota, Berman Center for Outcomes and Clinical Research, Minneapolis; Robert P. Byington, Ph.D., Wake Forest University School of Medicine, Winston-Salem, NC; Yves D. Rosenberg, M.D., National Heart, Lung, and Blood Institute, Bethesda, MD; and William T. Friedewald, M.D., Columbia University College of Physicians and Surgeons, New York) assume responsibility for the content of this article.

Footnotes

REFERENCES