Action to Control Cardiovascular Risk in Diabetes (ACCORD)

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial was a randomized, multicenter, double 2 x 2 factorial design study involving 10,251 middle-aged and older participants with type-2 diabetes who are at high risk for CVD events because of existing CVD or additional risk factors. The purpose of ACCORD was to determine if intensive glycemic control, intensive lipid management and intensive blood pressure control could prevent major cardiovascular events (myocardial infarction, stroke or cardiovascular death) in adults with type 2 diabetes mellitus. Secondary hypotheses included treatment differences in other cardiovascular outcomes, total mortality, microvascular outcomes, health-related quality of life and cost-effectiveness. The ACCORD trial failed to show a beneficial effect of intensive blood pressure or lipid therapy on the primary outcome, and intensive glycemia management actually increased mortality. The hypothesis underlying this ancillary study is that the failure of ACCORD to achieve its goal of reducing cardiovascular risk in diabetic patients through intensive management of hyperglycemia, dyslipidemia, and hypertension may be the result of variation in drug response due to genetic variation between individual participants. Benefits of intensive therapy may accrue to subsets of subjects with specific genetic variants predisposing to efficacious responses to particular therapeutic regimens, and harms may accrue to those with other variants predisposing to poor efficacy or adverse events. Identifying these variants could lead to a precision medicine approach to treating diabetes where each patient's genetic profile could identify the most efficacious treatment regimen with the lowest likelihood of adverse events. To test this hypothesis, a genome-wide genetic analysis was undertaken, incorporating both common variants distributed across the genome and rare variants targeted to exonic regions. Associations of genetic variants with short term responses to individual medicines as well as long term outcomes were investigated. The dataset is composed of genetic data from the ~6100 participants who agreed to participate in the ACCORD optional genetic studies and who allowed broad investigator access to their samples and the data derived from those samples, and from whom a DNA sample of sufficient quality was obtained. While a total of 8514 participants consented to the optional genetics studies, not all consented to broad investigator access, and those who did not are not included in this dataset, although they were also genotyped. Access to these additional genotypes can only be obtained by direct collaboration with the investigators of this study. Phenotype data used in the association analyses are derived from the ACCORD public release clinical data set, which has been made available through BioLINCC.]]>
Inclusion Criteria Type 2 diabetes mellitus defined according to the 1997 ADA criteria: Fasting plasma glucose > 126 mg/dl (> 7.0 mmol/l), or Symptoms of hyperglycemia with casual plasma glucose > 200 mg/dl (> 11.1 mmol/l), or 2 hour plasma glucose > 200 mg/dl (> 11.1 mmol/l) after a 75 gram oral glucose load HbA1c (obtained within 3 months prior to anticipated date of randomization): 7.5 to 11% if on insulin, < 1 u/kg plus on 0 or 1 oral agent, or if not on insulin, on 0, 1, or 2 oral agents 7.5 to 9% if on insulin < 1 u/kg plus on 2 oral agents, or if not on insulin plus on 3 oral agents, or if on insulin > 1 u/kg plus 0 oral agents Oral agents include: a) insulin secretagogues (sulfonylurea, meglitinides), b) biguanides, c) insulin enhancers (thiazolidinediones) The upper limits for HbA1c were selected to increase the likelihood of reaching the study's HbA1c targets. The lower limit was selected to allow for further reduction should the participant be assigned to the intensive glycemic group. Known diabetes duration > 3 months Stable diabetes therapy for > 3 months (dose of any 1 antihyperglycemic drug has not changed by more than two-fold and new agents have not been added within the previous 3 months) Age at Randomization: 40 to 79 years (inclusive) for anyone with a history of clinical cardiovascular disease (defined below in Item #6A), or 55 to 79 years (inclusive) for anyone without a history of clinical cardiovascular disease (defined below in Item #6A) At high risk of CVD events, defined as: Presence of clinical cardiovascular disease. previous myocardial infarction (MI) previous stroke History of coronary revascularization (e.g., coronary artery bypass graft surgery, stent placement, percutaneous transluminal coronary angioplasty, or laser atherectomy) History of carotid or peripheral revascularization (e.g., carotid endarterectomy, lower extremity atherosclerotic disease atherectomy, repair of abdominal aorta aneurysm, femoral or popliteal bypass) angina with ischemic changes (resting ECG), ECG changes on a graded exercise test (GXT), or positive cardiac imaging study, or If no clinical cardiovascular disease, evidence in the last 2 years suggesting a high likelihood of cardiovascular disease. Specifically, the presence of one of the following: Microalbuminuria Ankle brachial index < 0.9 (by simple palpation) LVH by ECG or ECHO > 50% stenosis of a coronary, carotid, or lower extremity artery, or The presence of at least 2 of the following factors that increase CVD risk: On lipid lowering medication or untreated LDL-C < 130 mg/dl (3.38 mmol/l) Low HDL-C (< 40 mg/dl (1.04 mmol/l) for men and < 50 mg/dl (1.29 mmol/l) for women) On BP lowering medication or untreated SBP > 140 mm Hg or DBP > 95 mm Hg Current cigarette smoking Body mass index > 32 kg/m2 Note: Category A represents secondary prevention participants. Categories B and C together represent primary prevention participants. Exclusion Criteria History of hypoglycemic coma/seizure within last 12 months Hypoglycemia requiring 3rd party assistance in last 3 months with concomitant glucose < 60 mg/dl (3.3 mmol/l) History consistent with type 1 diabetes Unwilling to do frequent capillary blood glucose self-monitoring or unwilling to inject insulin several times a day BMI > 45 kg/m2 Serum Creatinine > 1.5 mg/dl (132.6 umol/l) obtained within the previous 2 months Transaminase > 2 times upper limit of normal or active liver disease Any ongoing medical therapy with known adverse interactions with the glycemic interventions (e.g., corticosteroids, protease inhibitors) Cardiovascular event or procedure (as defined for study entry) or hospitalization for unstable angina within last 3 months Current symptomatic heart failure, history of NYHA Class III or IV congestive heart failure at any time, or ejection fraction (by any method) < 25% A medical condition likely to limit survival to less than 3 years or a malignancy other than non-melanoma skin cancer within the last 2 years Any factors likely to limit adherence to interventions. For example, dementia alcohol or substance abuse plans to move in the next 2 years history of unreliability in medication taking or appointment keeping significant concerns about participation in the study from spouse, significant other, or family members lack of support from primary health care provider Failure to obtain informed consent from participant Currently participating in another clinical trial. Note: Patient must wait until the completion of his/her activities or the completion of the other trial before being screened for ACCORD Living in the same household as an already randomized ACCORD participant Any organ transplant Weight loss > 10% in last 6 months Pregnancy, currently trying to become pregnant, or of child-bearing potential and not practicing birth control Participants with recurrent requirements for phlebotomy or transfusion of red blood cells. ]]>
Subject recruitment began in January, 2001. Subject recruitment occurred in two phases: 1174 patients were recruited during a 20-week period from January to June 2001, and 9077 patients were recruited from February 2003 to October 2005. After an interim safety assessment in January, 2008, the intensive glycemia treatment strategy was stopped in February of 2008 and all subjects were switched to standard glycemia treatment due to an excess of mortality in the intensive glycemia arm. The mean duration of follow-up at the time the intensive treatment strategy was stopped was 3.5 years. In person follow-up ended in June of 2009 after a mean duration of follow-up of 4.7 years.]]>