Long-Term Effects of Intensive Glucose Lowering on Cardiovascular Outcomes

T h e n e w e n g l a n d j o u r n a l o f m e d i c i n eoriginal articleLong-Term Effects of Intensive Glucose

Lowering on Cardiovascular OutcomesThe ACCORD Study Group*A b s t r a c t

The members of the writing group (Hertzel C. Gerstein, M.D., McMaster Uni- versity and Hamilton Health Sciences, Hamilton, ON, Canada; Michael E. Miller, Ph.D., Wake Forest University School of Medicine, Winston-Salem, NC; Saul Ge- nuth, M.D., Case Western Reserve Uni- versity, Cleveland; Faramarz Ismail-Beigi, M.D., Ph.D., Case Western Reserve Uni- versity, Cleveland; John B. Buse, M.D., Ph.D., University of North Carolina, Cha- pel Hill; David C. Goff, Jr., M.D., Ph.D., Wake Forest University School of Medi- cine, Winston-Salem, NC; Jeffrey L. Prob- stfield, M.D., University of Washington, Seattle; William C. Cushman, M.D., Memphis Veterans Affairs Medical Cen- ter, Memphis; Henry N. Ginsberg, M.D., Columbia University College of Physi- cians and Surgeons, New York; J. Thom- as Bigger, M.D., Columbia University Col- lege 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 Medi- cine, Winston-Salem, NC; Yves D. Rosen- berg, M.D., National Heart, Lung, and Blood Institute, Bethesda, MD; and Wil- liam T. Friedewald, M.D., Columbia Uni- versity College of Physicians and Sur- geons, New York) assume responsibility for the content of this article. Address reprint requests to Dr. Gerstein at Mc- Master University, Department of Medi- cine, HSC 3V38, 1200 Main St. W., Hamil- ton, ON L8N 3Z5, Canada, or at gerstein@ mcmaster.ca.

*Members of the Action to Control Car- diovascular Risk in Diabetes (ACCORD) Study Group are listed in the Supple- mentary Appendix, available at NEJM.org.

N Engl J Med 2011;364:818-28.

Copyright 2011 Massachusetts Medical Society.

BackgroundIntensive glucose lowering has previously been shown to increase mortality among persons with advanced type 2 diabetes and a high risk of cardiovascular disease. This report describes the 5-year outcomes of a mean of 3.7 years of intensive glucose low- ering on mortality and key cardiovascular events.MethodsWe randomly assigned participants with type 2 diabetes and cardiovascular disease or additional cardiovascular risk factors to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level of 7 to7.9%). After termination of the intensive therapy, due to higher mortality in the intensive-therapy group, the target glycated hemoglobin level was 7 to 7.9% for all participants, who were followed until the planned end of the trial.ResultsBefore the intensive therapy was terminated, the intensive-therapy group did not differ signif icantly from the standard-therapy group in the rate of the primary out- come (a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) (P = 0.13) but had more deaths from any cause (primarily car- diovascular) (hazard ratio, 1.21; 95% confidence interval [CI], 1.02 to 1.44) and fewer nonfatal myocardial infarctions (hazard ratio, 0.79; 95% CI, 0.66 to 0.95). These trends persisted during the entire follow-up period (hazard ratio for death, 1.19;95% CI, 1.03 to 1.38; and hazard ratio for nonfatal myocardial infarction, 0.82; 95% CI, 0.70 to 0.96). After the intensive intervention was terminated, the median gly- cated hemoglobin level in the intensive-therapy group rose from 6.4% to 7.2%, and the use of glucose-lowering medications and rates of severe hypoglycemia and other adverse events were similar in the two groups.ConclusionsAs compared with standard therapy, the use of intensive therapy for 3.7 years to target a glycated hemoglobin level below 6% reduced 5-year nonfatal myocardial infarc- tions but increased 5-year mortality. Such a strategy cannot be recommended for high-risk patients with advanced type 2 diabetes. (Funded by the National Heart, Lung and Blood Institute; ClinicalTrials.gov number, NCT00000620.)

intensi v e glucose l ow er ing a nd c a r diova scul a r e v ent sype 2 diabetes mellitus is a strong, independent risk factor for cardiovascular disease and death,1 and many epidemio-logic analyses have identif ied a progressive rela- tionship between hyperglycemia and these out- comes.2-5 The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was designed to determine whether a strategy of targeting nor- mal glycated hemoglobin levels (i.e., 10 kg since baseline 861 (17.1) 699 (15.8) 426 (8.5) 452 (10.1) no. (%)

Body-mass index 32.25.533.56.233.16.232.25.532.55.932.56.0

Waist circumference (cm) 106.713.9109.615.3109.115.3106.813.8107.514.8107.714.9

Blood pressure mm HgSystolic136.216.9127.717.2129.317.4136.417.2128.517.4128.516.5

Diastolic 74.810.667.310.868.310.575.010.768.110.867.710.1

Glycated hemoglobin %

Mean 8.31.16.61.07.41.28.31.17.71.17.81.2

Median 8.16.47.28.17.57.6

Fasting serum glucose mg/dl 174.955.9117.045.0143.455.4175.756.5153.453.4154.955.2

Cholesterol g/dl

Low-density lipoprotein 104.933.990.834.087.933.1104.933.890.734.587.933.7

High-density lipoprotein

Women 47.213.048.613.249.513.446.912.247.613.649.013.9

Men 38.49.540.110.840.410.438.89.739.610.840.511.2

Total183.441.9164.842.3163.142.1183.241.6167.244.1164.042.2

Median triglycerides mg/dl 190.9148.4 154.6102.0160.3125.0189.4148.8175.5151.5166.0114.8

Potassium mg/dl 4.50.44.40.44.40.44.50.74.40.54.40.5

Serum creatinine mg/dl 0.90.21.10.41.10.40.90.21.10.41.10.4

Alanine aminotransferase >3 times ULN52 (1.0) 27 (0.6) 77 (1.5) 21 (0.5) no. (%)

* Baseline measurements include all participants who underwent randomization. Pretransition measurements are the last measurements made before the transition, on February 5, 2008, for participants with at least one measurement. Post-transition measurements are the last measurements made for participants for whom measurements were made during the post-transition period. Plusminus values are meansSD except where otherwise noted. To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for cholesterol to millimoles per liter, multiply by 0.02586. To convert the values for triglycerides to millimoles per liter, multiply by 0.01129. To convert the values for potassium to millimoles per liter, multiply by 0.2558. To convert the values for creatinine to micromoles per liter, multiply by 88.4. ULN denotes upper limit of the normal range. Body-mass index is the weight in kilograms divided by the square of the height in meters.to post-transition hazard ratios, 1.06; 95% CI,

0.76 to 1.46; P = 0.74). There was a possible dif- ference in the effect of the intensive therapy on the pretransition primary outcome among partici- pants 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 fenof ibrate 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. How- ever, there was evidence of an interaction between the intensive glucose-lowering group and the in- tensive blood-pressurelowering group with re- spect 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,822

n engl j med 364;9 nejm.org march 3, 2011

A Primary Outcome before TransitionHazard ratio, 0.90 (95% CI, 0.781.03)10020

80100

400 1 2 3 4 5 6 7 8

20

0

012345678

Years since RandomizationNo. at RiskStandard 5123 4912 4729 3533 2001 457 436 14

Intensive 5128 4911 4743 3544 2001 498 483 19B Primary Outcome until End of StudyHazard ratio, 0.91 (95% CI, 0.811.03)10020

80100

600 1 2 3 4 5 6 7 8

20

0

012345678

Years since RandomizationNo. at RiskStandard 5123 4912 4729 4580 3774 2251 729 407 217Intensive 5128 4911 4743 4594 3750 2277 734 457 239C Primary Outcome after TransitionHazard ratio, 0.94 (95% CI, 0.741.21)10010

80

0

40012

20

0

012

Years since TransitionNo. at RiskStandard 47424611

Intensive 46904552

D Death from Any Cause before TransitionHazard ratio, 1.21 (95% CI, 1.021.44)10020

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400 1 2 3 4 5 6 7 8

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Years since RandomizationNo. at RiskStandard 5123 5071 5006 3807 2217 528 518 18

Intensive 5128 5066 4992 3767 2190 551 539 21E Death from Any Cause until End of StudyHazard ratio, 1.19 (95% CI, 1.031.38)10020

80100

400 1 2 3 4 5 6 7 8

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012345678

Years since RandomizationNo. at RiskStandard 5123 5017 5006 4918 4127 2494 842 477 266

Intensive 5128 5066 4992 4855 4053 2479 814 496 263F Death from Any Cause after TransitionHazard ratio, 1.15 (95% CI, 0.871.51)10010

80

0

40012

20

0

012

Years since TransitionNo. at RiskStandard 44144197

Intensive 44274218

Figure 1. KaplanMeier Curves for the Primary Outcome and Death from Any Cause.The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. Panels A and D show the incidence rates from ran- domization until the time of transition, Panels B and E show the rates from randomization until the end of the trial, and Panels C and F show the rates for the post-transition peri- od. Plots for the post-transition period (Panels C and F) are included for descriptive purposes only; they cannot be used to infer any effect of the intensive therapy in this period.

TYPE: Line Combo 4-C H/T broadsideAUTHOR, PLEASE NOTE:Figure has been redrawn and type has been reset.Please check carefully.JOB: 36409ISSUE: 03-03-110.98

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0.03

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0.43

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0.88 (0.771.00)0.90 (0.811.01)0.97 (0.711.33)0.86 (0.651.13)1.19 (0.961.47)1.09 (0.911.32)0.50

1.002.00

Intensive TherapyBetter

Standard TherapyBetterFigure 2. Hazard Ratios for the Prespecif ied Primary and Secondary Outcomes.The effect of intensive glucose-lowering therapy is shown from randomization until the time of transition and from randomization until the end of the trial. Squares represent hazard ratios, and horizontal bars represent 95% confidence intervals. CHF denotes congestive heart failure.

this interaction was characterized by a margin- ally higher mortality rate in the intensive glucose- lowering group than in the standard glucose- lowering group among participants also assigned to the intensive blood-pressurelowering group (hazard ratio, 1.45; 95% CI, 1.00 to 2.12; P = 0.05) but not among those also assigned to the stan- dard blood-pressurelowering group (hazard ra- tio, 0.78; 95% CI, 0.52 to 1.18; P = 0.24).D i s c u s s i o nThe 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 f indings indicate that in a high-risk population such as this, a mean of 3.7 years of intensive therapy con- sisting of multiple glucose-lowering methods to target normal glycated hemoglobin levels (i.e., below 6.0%) does not result in a signif icantly lower number of major cardiovascular events af- ter 5 years than does an approach that uses sim- ilar methods to target levels that are more typi- cally achieved in persons in the United States and Canada (i.e., 7 to 7.9%). Indeed, the intensive ap- proach led to more deaths. Effects on the primary outcome were similar during the 3.7-year glucose-824

n engl j med 364;9 nejm.org march 3, 2011Table 2. Causes of Death.*

During PretransitionFrom RandomizationCause of DeathPerioduntil End of StudyIntensive Standard Intensive StandardTherapyTherapyTherapyTherapynumber (percent)

Any283 (5.5) 232 (4.5) 391 (7.6) 327 (6.4)

Cardiovascular disease

Unexpected or presumed cardiovascular disease 89 (1.7) 78 (1.5) 124 (2.4) 103 (2.0)

Fatal myocardial infarction 20 (0.4) 12 (0.2) 24 (0.5) 14 (0.3)

Fatal congestive heart failure26 (0.5) 20 (0.4) 32 (0.6) 25 (0.5)

Fatal procedure for cardiovascular disease 11 (0.2) 5 (0.1) 14 (0.3) 7 (0.1)

Fatal arrhythmia 4 (0.1) 12 (0.2) 6 (0.1) 18 (0.4)

Fatal procedure for noncardiovascular disease 1 (