ACCORD
Action to Control Cardiovascular Risk in Diabetes - Effects of Intensive Glucose Lowering in Type 2 Diabetes
Year of Publication: 2008
Authors: Hertzel C. Gerstein, Michael E. Miller, Robert P. Byington, ..., William T. Friedewald; The Action to Control Cardiovascular Risk in Diabetes Study Group
Journal: New England Journal of Medicine
Citation: N Engl J Med 2008;358:2545-59
Link: https://doi.org/10.1056/NEJMoa0802743
PDF: https://www.nejm.org/doi/pdf/10.1056/NEJ...ticleTools=true
PDF: Clinical Question
Does intensive glucose-lowering therapy targeting HbA1c below 6.0% reduce cardiovascular events compared with standard therapy targeting HbA1c 7.0-7.9% in middle-aged and older patients with type 2 diabetes and established cardiovascular disease or additional cardiovascular risk factors?
Study Overview
Objective
To determine whether intensive glucose lowering (HbA1c <6.0%) reduces cardiovascular events compared to standard therapy (HbA1c 7.0-7.9%) in patients with type 2 diabetes and established cardiovascular disease or risk factors
Study Summary
- Intensive glucose lowering increased mortality by 22% compared to standard therapy (5.0% vs 4.0%, HR 1.22, p=0.04)
- No significant reduction in primary cardiovascular outcome (6.9% vs 7.2%, HR 0.90, p=0.16)
- Trial was terminated early due to increased mortality in the intensive therapy group
Intervention
Intensive glucose lowering targeting HbA1c <6.0% using multiple medications vs standard therapy targeting HbA1c 7.0-7.9%
Patients per Arm
5,128 intensive, 5,123 standard
Bottom Line
Intensive glucose lowering to target HbA1c <6.0% did NOT significantly reduce major cardiovascular events but INCREASED all-cause mortality by 22% (HR 1.22, p=0.04) after mean 3.5 years. The trial was stopped early due to this excess mortality. While nonfatal MI was reduced, this was offset by increased cardiovascular death. This landmark trial identified a previously unrecognized harm of aggressive glucose lowering in high-risk diabetics.
Major Points
- Primary composite outcome (nonfatal MI, nonfatal stroke, CV death) not significantly different: 6.9% intensive vs 7.2% standard (HR 0.90, p=0.16)
- ALL-CAUSE MORTALITY INCREASED with intensive therapy: 5.0% vs 4.0% (HR 1.22, 95% CI 1.01-1.46, p=0.04)
- CV death also increased with intensive therapy: 2.6% vs 1.8% (HR 1.35, 95% CI 1.04-1.76, p=0.02)
- Trial stopped early (February 2008) by DSMB due to safety concerns, 17 months before scheduled completion
- Nonfatal MI was REDUCED with intensive therapy: 3.6% vs 4.6% (HR 0.76, p=0.004)
- No difference in nonfatal stroke: 1.3% vs 1.2% (HR 1.06, p=0.74)
- Achieved HbA1c: 6.4% intensive vs 7.5% standard (difference maintained throughout follow-up)
- Hypoglycemia requiring medical assistance much higher with intensive therapy: 10.5% vs 3.5% (p<0.001); requiring any assistance 16.2% vs 5.1%
- Weight gain >10kg more common with intensive therapy: 27.8% vs 14.1% (p<0.001)
- 91.2% of intensive group received rosiglitazone vs 57.5% standard - drug safety questions raised
- Exploratory analyses did not identify clear explanation for mortality finding
- Subgroups without prior CVD or with baseline HbA1c ≤8.0% showed possible primary outcome benefit (hypothesis-generating)
Design
Study Type: Multicenter randomised controlled trial with double 2×2 factorial design (blood pressure and lipid interventions tested concurrently)
Randomization: 1
Blinding: Open-label glucose intervention; outcomes adjudicated by central committee blinded to treatment assignment; central laboratory blinded for HbA1c analysis
Enrollment Period: January-June 2001 (phase 1: 1174 patients); February 2003-October 2005 (phase 2: 9077 patients)
Follow-up Duration: Mean 3.5 years (median 3.4 years); stopped early February 2008
Centers: 77
Countries: United States, Canada
Sample Size: 10251
Analysis: Intention-to-treat; Cox proportional-hazards regression with stratification for BP trial/lipid trial assignment, clinical network, and prior CVD; likelihood-ratio tests
Inclusion Criteria
- Type 2 diabetes mellitus
- HbA1c ≥7.5%
- Age 40-79 years with established cardiovascular disease
- OR age 55-79 years with anatomical evidence of significant atherosclerosis, albuminuria, left ventricular hypertrophy, or ≥2 additional CV risk factors (dyslipidemia, hypertension, current smoking, obesity)
Exclusion Criteria
- Frequent or recent serious hypoglycemic events
- Unwillingness to do home glucose monitoring or inject insulin
- Body mass index >45 kg/m²
- Serum creatinine >1.5 mg/dL (133 µmol/L)
- Other serious illness
Baseline Characteristics
| Characteristic | Standard Therapy | Intensive Therapy |
|---|---|---|
| Age - years | 62.2 ± 6.8 | 62.2 ± 6.8 |
| Sex - Female | 38.4% | 38.7% |
| Median duration of diabetes - years | 10 | 10 |
| Previous cardiovascular event | 34.8% | 35.6% |
| Previous congestive heart failure | 4.8% | 4.9% |
| Race - White | 64.5% | 64.4% |
| Race - Black | 18.9% | 19.7% |
| Race - Hispanic | 7.4% | 7.0% |
| Education - Less than high school | 14.0% | 15.7% |
| Education - College degree or higher | 26.4% | 25.5% |
| Smoking - Current | 13.7% | 14.3% |
| Smoking - Former | 44.0% | 44.4% |
| Weight - kg | 93.6 ± 18.7 | 93.5 ± 18.7 |
| BMI - kg/m² | 32.2 ± 5.5 | 32.2 ± 5.5 |
| Waist circumference - cm | 106.8 ± 13.8 | 106.8 ± 14.3 |
| Systolic BP - mmHg | 136.5 ± 17.2 | 136.2 ± 17.0 |
| Diastolic BP - mmHg | 75.0 ± 10.7 | 74.8 ± 10.6 |
| Baseline insulin use | 35.7% | 34.1% |
| Baseline metformin use | 60.0% | 59.7% |
| Baseline sulfonylurea use | 49.4% | 50.8% |
| Baseline TZD use | 19.2% | 19.5% |
| Baseline antihypertensive use | 86.0% | 84.9% |
| Baseline ACE inhibitor use | 53.0% | 53.0% |
| Baseline aspirin use | 54.1% | 54.8% |
| Baseline beta-blocker use | 29.9% | 28.7% |
| Baseline statin use | 62.4% | 61.7% |
| HbA1c - mean | 8.3 ± 1.1% | 8.3 ± 1.1% |
| HbA1c - median | 8.1% | 8.1% |
| Fasting glucose - mg/dL | 175.7 ± 56.5 | 174.9 ± 56.0 |
| Total cholesterol - mg/dL | 183.3 ± 41.6 | 183.3 ± 42.1 |
| LDL cholesterol - mg/dL | 104.9 ± 33.8 | 104.9 ± 34.0 |
| HDL cholesterol (women) - mg/dL | 46.9 ± 12.2 | 47.2 ± 13.0 |
| HDL cholesterol (men) - mg/dL | 38.8 ± 9.8 | 38.4 ± 9.5 |
| Median triglycerides - mg/dL | 154 | 156 |
| Serum creatinine - mg/dL | 0.9 ± 0.2 | 0.9 ± 0.2 |
Arms
| Field | Intensive Therapy | Control |
|---|---|---|
| Intervention | Comprehensive individualized glucose-lowering strategy targeting HbA1c <6.0% using combinations of metformin, secretagogues (glimepiride, repaglinide), TZDs (rosiglitazone), alpha-glucosidase inhibitors, incretins (exenatide), and insulin. Monthly visits for first 4 months, then every 2 months. Mean 4.4 medication adjustments per year. | Glucose-lowering strategy targeting HbA1c 7.0-7.9% using similar drug classes with fewer medications and combinations. Visits every 4 months. Mean 2.0 medication adjustments per year. |
| Duration | Mean 3.5 years (stopped early) | Mean 3.5 years |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| First occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes | Primary | 371/5123 (7.2%); 2.29% per year | 352/5128 (6.9%); 2.11% per year | 0.9 | 0.16 |
| Death from any cause | Secondary | 203/5123 (4.0%); 1.14% per year | 257/5128 (5.0%); 1.41% per year | 1.22 | 0.04 |
| Death from cardiovascular causes | Secondary | 94/5123 (1.8%); 0.56% per year | 135/5128 (2.6%); 0.79% per year | 1.35 | 0.02 |
| Nonfatal myocardial infarction | Secondary | 235/5123 (4.6%); 1.45% per year | 186/5128 (3.6%); 1.11% per year | 0.76 | 0.004 |
| Nonfatal stroke | Secondary | 61/5123 (1.2%); 0.37% per year | 67/5128 (1.3%); 0.39% per year | 1.06 | 0.74 |
| Fatal or nonfatal congestive heart failure | Secondary | 124/5123 (2.4%); 0.75% per year | 152/5128 (3.0%); 0.90% per year | 1.18 | 0.17 |
| Hypoglycemia requiring medical assistance | Adverse | 179 (3.5%) | 538 (10.5%) | <0.001 | |
| Hypoglycemia requiring any assistance | Adverse | 261 (5.1%) | 830 (16.2%) | <0.001 | |
| Weight gain >10 kg | Adverse | 713/5042 (14.1%) | 1399/5036 (27.8%) | <0.001 | |
| Fluid retention | Adverse | 3378/5054 (66.8%) | 3541/5053 (70.1%) | <0.001 | |
| Any nonhypoglycemic serious adverse event | Adverse | 82 (1.6%) | 113 (2.2%) | 0.03 | |
| ALT >3x ULN | Adverse | 77/5061 (1.5%) | 51/5065 (1.0%) | 0.02 |
Subgroup Analysis
Mortality effect consistent across all prespecified subgroups (no heterogeneity). For primary outcome, possible heterogeneity suggested: patients without prior CVD (P interaction=0.04) and those with baseline HbA1c ≤8.0% (P interaction=0.03) may have had fewer events with intensive therapy. These findings are hypothesis-generating only.
Criticisms
- Open-label design for glucose intervention may have influenced patient management and outcomes
- Rapid reduction in HbA1c (1.4% drop in 4 months) may have contributed to adverse outcomes rather than achieved level
- High use of rosiglitazone (91% in intensive group) raises questions about drug-specific vs glycemic target effects
- Multiple drug combinations at high doses may have caused unmeasured drug interactions
- Hypoglycemia much higher in intensive group (10.5% vs 3.5% requiring medical assistance) and may have contributed to CV mortality
- Unable to identify clear mechanism for mortality excess despite extensive exploratory analyses
- Study not designed to test individual components of intensive strategy
- Population limited to high-risk patients with either established CVD or multiple CV risk factors; results may not apply to lower-risk diabetics (only ~35% had prior CV event, so trial included a large high-risk primary-prevention subgroup)
- Concurrent BP and lipid trials within factorial design complicate interpretation
Funding
National Heart, Lung, and Blood Institute (N01-HC-95178 through N01-HC-95184, IAA-Y1-HC-9035, IAA-Y1-HC-1010); National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Aging; National Eye Institute; Centers for Disease Control and Prevention; General Clinical Research Centers. Study medications, equipment, or supplies from Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca, Bayer HealthCare, Closer Healthcare, GlaxoSmithKline, King Pharmaceuticals, Merck, Novartis, Novo Nordisk, Omron Healthcare, Sanofi-Aventis, and Schering-Plough.
Based on: ACCORD (New England Journal of Medicine, 2008)
Authors: Hertzel C. Gerstein, Michael E. Miller, Robert P. Byington, ..., William T. Friedewald; The Action to Control Cardiovascular Risk in Diabetes Study Group
Citation: N Engl J Med 2008;358:2545-59
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