ACCORD

From Wiki Journal Club

Gerstein HC, et al. "Effects of Intensive Glucose Lowering in Type 2 Diabetes". The New Published
England Journal of Medicine. 2008. 358(24):2545-59.
PubMed (http://www.ncbi.nlm.nih.gov/pubmed/18539917) • Full text
(http://www.nejm.org/doi/full/10.1056/NEJMoa0802743) • PDF
(http://www.nejm.org/doi/pdf/10.1056/NEJMoa0802743)

Clinical Question
Contents
In patients with T2DM, does intensive glycemic control targeting
a HbA1c <6% versus standard glycemic control targeting a 1 Clinical Question
HbA1c 7-7.9% reduce the risk of CV events? 2 Bottom Line
3 Major Points
4 Guidelines
Bottom Line 5 Design
6 Population
In patients with T2DM, intensive glycemic control (target HbA1c 6.1 Inclusion Criteria
<6%) increases mortality compared to standard control (target 6.2 Exclusion Criteria
A1c 7-7.9%). 7 Interventions
8 Outcomes
8.1 Primary Outcome
Major Points 8.2 Secondary Outcomes
8.3 Additional Analyses
Cardiovascular disease is a major cause of morbidity and 9 Criticisms
mortality in patients with T2DM. The 2005 EDIC (an extension 10 Funding
of the 1993 DCCT trial) demonstrated that improved glycemic 11 Further Reading
control reduces the rate of long-term CVD in patients with
T1DM. However, this macrovascular outcome had not been
replicated in similar trials in patients with T2DM (including the 1998 UKPDS 33). Whether patients with
T2DM have reduced incidence of CVD with near-euglycemic control (i.e. pushing the HbA1C goal <7%)
was unclear.

The 2008 Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial randomized 10,251 patients
with long-standing T2DM to either intensive (HbA1c <6%) or standard glycemic control (HbA1c 7-7.9%).
After a median follow-up of 3.7 years, the trial was stopped early because intensive glycemic control was
associated with increased all-cause (1.41% vs. 1.14%; P=0.04; NNH 370) and CV mortality (0.79% vs.
0.56%; P=0.02). The concurrently published ADVANCE trial found no CV benefit in a similar population,
but it did not demonstrate increased mortality. Subsequently, VADT (2009) did not demonstrate a CV
mortality benefit in T2DM VA patients in a similar trial design. Whether the mortality increase in ACCORD
was resultant to the trial's heavy use of TZDs (i.e. rosiglitazone), which have been associated in some studies
with increased CV mortality,
[1] is unclear.[2]

As a result, intensive glycemic control in T2DM is only recommended for some low-risk groups.
[3]
Guidelines
ADA Medical Care in DM (2013)
[3]

Goal A1C <7% in non-pregnant adults to reduce microvascular and macrovascular disease
complications (level B)
Goal A1C <6.5% for selected patients, provided no hypoglycemia or other adverse events (level C)
Goal A1C <8% for those with previous severe hypoglycemia, limited life expectancy, advanced
microvascular or macrovascular complications, comorbidities, and long-standing difficult-to-control
DM despite appropriate education and multiple agents including insulin (level B)

Design
Multicenter, double-blinded, two-by-two factorial, randomized controlled trial
N=10,251
Intensive (n=5,128)
Standard (n=5,123)
Setting: 77 North American centers
Enrollment: 2001-2005
Mean follow-up: 3.5 years (stopped after safety committee recommended discontinuation of intensive
therapy)
Primary outcome: Annual rate of nonfatal MI or nonfatal stroke or CV death

Population
Inclusion Criteria
Type 2 diabetes mellitus
Hemoglobin A1c ≥7.5%
Age 40-79 years with CAD or 55-79 years with
Anatomical evidence of significant atherosclerosis
Albuminuria
LVH
≥2 cardiovascular risk factors (dyslipidemia, HTN, current smoking, obesity)

Exclusion Criteria

Frequent or recent serious hypoglycemic events

Unwillingness to perform home glucose monitoring or insulin injections
BMI >45
Cr >1.5mg/dl
Serious illness

Interventions
Randomized to intensive (targeting HbA1c <6%) or standard (HbA1c 7-7.9%) therapy

46% randomized to intensive (SBP <120) vs. standard (SBP <140) blood pressure therapy
54% randomized to fenofibrate vs. placebo; all received statin to achieve good LDL control
 Intensive therapy group attended monthly visits for 4 months, then every 2 months, with additional
visits and telephone calls as needed
Standard therapy group had glycemic control visits every 4 months

Outcomes
Comparisons are intensive vs. standard therapy.

Primary Outcome
Annual rate of nonfatal MI or nonfatal stroke or CV death
2.11% vs. 2.29% (HR 0.90; 95% CI 0.78-1.04; P=0.16)

Secondary Outcomes

Annual rate of all-cause mortality

1.41% vs. 1.14% (HR 1.22; 95% CI 1.01-1.46; P=0.04; NNH 370)

Annual rate of CV mortality

0.79% vs. 0.56% (HR 1.35; 95% CI 1.04-1.76; P=0.02)

Annual rate of nonfatal MI

1.11% vs. 1.45% (HR 0.76; 95% CI 0.62-0.92; P=0.004)

Annual rate of nonfatal stroke

0.39% vs. 0.37% (HR 1.06; 95% CI 0.75-1.50; P=0.74)

Annual rate of HF
0.90% vs. 0.75% (HR 1.18; 95% CI 0.93-1.49; P=0.17)

Additional Analyses

Adverse events
Hypoglycemia

Requiring medical assistance: 10.5% vs. 3.5% (P<0.001)

Requiring any assistance: 16.2% vs. 5.1% (P<0.001)

Heart failure: 3.0% vs. 2.4% (P=0.10)

MVC with patient as driver: 0.2% vs. 0.3% (P=0.40)
Non-hypoglycemic serious adverse event: 2.2% vs. 1.6% (P=0.03)
Fluid retention: 70.1% vs. 66.8% (P<0.001)

Clinical measures
Weight gain of >10 kg from baseline: 27.8% vs. 14.1% (P<0.001)
ALT > 3 times ULN: 1.0% vs. 1.5% (P=0.02)
LDL cholesterol: 90.8 mg/dL vs. 90.6 mg/dL (P=0.74)
Blood pressure

Systolic: 126.4 mmHg vs. 127.4 mmHg (P=0.002)

Diastolic: 66.9 mmHg vs. 67.7 mmHg (P<0.001)

Statistical analysis not presented by the authors for the following data.
Medications
Metformin: 94.7% vs. 86.9%
Secretagogue: 86.6% vs. 73.8%

Glimepiride: 78.2% vs. 67.6%

Repaglinide: 50.2% vs. 17.7%

TZD: 91.7% vs. 58.3%

Rosiglitazone: 91.2% vs. 57.5%

Alpha glucosidase inhibitor: 23.2% vs. 5.1%

Incretin: 17.8% vs. 4.9%

Exenatide: 12.1% vs. 4.0%

Insulin: 77.3% vs. 55.4%

Bolus insulin: 55.3% vs. 35.0%

Criticisms
Increased mortality could have been due to rosiglitazone (91% vs 57% use) or other specific agents or
polypharmacy in the intensive group[2]
Disproportionate weight gain between the groups may have influenced the outcome[2]
No report of blood pressure medications used specifically ACE-inhibitors and ARBs, which confer
greater benefit for diabetics than other agents[2]
Fewer patients in the intensive treatment arm received ACE-inhibitors (69.7% vs 71.9%)

Funding
Funding, medications, equipment, and supplies were provided by NIH grants from the NHLBI, other NIH
departments, the CDC, General Clinical Research Centers, Abbott Laboratories, Amylin Pharmaceutical,
AstraZeneca, Bayer HealthCare, Closer Healthcare, GlaxoSmithKline, King Pharmaceuticals, Merck,
Novartis, Novo Nordisk, Omron Healthcare, Sanofi-Aventis, and Schering-Plough.

Further Reading
1. Nissen SE and Wolski K. "Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from
Cardiovascular Causes." The New England Journal of Medicine. 2007;356:2457-2471
(http://www.nejm.org/doi/full/10.1056/NEJMoa072761)
2. Multiple authors. "Correspondence: Intensive glucose control in type 2 diabetes." The New England
Journal of Medicine. 2008;359:1519-1521. (http://www.nejm.org/doi/full/10.1056/NEJMc081457)
3. Multiple authors. "Executive summary: Standards of medical care in diabetes--2013" Diabetes Care
2013;36(supp 1):s4-s10. (http://care.diabetesjournals.org/content/36/Supplement_1/S4.full.pdf)

Retrieved from "http://www.wikijournalclub.org/w/index.php?title=ACCORD&oldid=31097"

Categories: Usable articles Endocrinology

This page was last modified on 12 September 2018, at 00:39.