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Diabetes NewsJuly 2011

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A1C and Cardiovascular Outcomes in Type 2 Diabetes

Diabetes Care • January 2011 

Type 2 diabetes is associated with an increased risk of microvascular complications, such as nephropathy, neuropathy and retinopathy, as well as microvascular complications including myocardial infarction (MI) and stroke. Diabetic patients who have not had a previous MI have the same risk of an infarction as non-diabetic patients who have had a previous MI. Cardiovascular disease complications are the most common cause of mortality in type 2 diabetic patients, accounting for 52% of the deaths in this population.

Tighter glycemic control and lower A1C levels decrease the risk of microvascular complications. The American Diabetes Association recommends a target A1C <7%, whereas the American Association of Clinical Endocrinologists recommends an A1C target of ≤6.5%. Despite these established guidelines, questions remain regarding the ideal A1C target for minimizing cardiovascular events in type 2 diabetes. Observational studies have suggested a direct association between hyperglycemia and cardiovascular events, whereas three large, randomized trials failed to establish a cardiovascular benefit for intensive glycemic control. The Veterans Affairs Diabetes Trial (VADT) randomly assigned subjects to intensive glycemic control (target A1C ≤6.0%) verses standard treatment (target A1C 8%-9%) and found no significant difference between the treatment arms for major cardiovascular events or all-cause mortality. Similarly, the Action in Diabetes and Vascular Disease Trial compared a target A1C of ≤6.5% with standard care and found no significant difference in macrovascular events. Finally, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial compared a target A1C of ≤6.0% to a target of 7.0%-7.9% in the standard arm. The trial was halted early because of a significant increase in all-cause death and cardiovascular death in the intensively treated arm.

This study investigated whether the increased risk associated with intensive glycemic control found in the ACCORD trial is observed in a managed-care population. Glycemic control was defined as the mean A1C level for each patient measured over three years to mimic the average follow-up period in the ACCORD study.  

Objective - Type 2 diabetes is associated with increased cardiovascular risk. The role of aggressive glycemic control in preventing cardiovascular events is unclear. A nested case-control study was used to evaluate the association between average A1C and cardiovascular outcomes.

Research Design and Methods - The relationship between glycemic control and cardiovascular events using a nested case-control design was investigated. Adults with type 2 diabetes were identified among members of Kaiser Permanente Southern California (KPSC). Type 2 diabetes was identified on ICD-9 diagnosis codes and either A1C >7.5% or prescriptions for hypoglycemic agents. Case subjects were defined based on nonfatal myocardial infarction, nonfatal stroke, or death attributed to cardiovascular events during a three year window. Four type 2 diabetes control subjects were matched to each case subject based upon age, sex, and index date for the corresponding case. A conditional logistic regression model was used to estimate the odds ratio of cardiovascular events and compare three patient groups based upon average A1C measured in the preindex period (≤6%, >6%-8% and >8%).   

Data were derived from Kaiser Permanente Southern California Health Plan, which contains information on patient demographics, diagnoses, prescriptions, laboratory results and medical and hospital encounters. The racial composition is as follows: 42.9% non-Hispanic white; 23.2% white; 14.4% black; 9.6%Asian/Pacific Islander; 0.2% American Indian/Alaskan; 9.4% other and 0.3% two or more races.

Adult patients (aged ≥18 years old) with type 2 diabetes were identified based upon two recorded type 2 diabetes diagnoses between January 2002 and December 2007 and either an A1C ≥7.5% or a prescription for oral hypoglycemic medication or insulin. Patients with a diagnosis of polycystic ovarian syndrome, gestational diabetes, or serious illness including HIV/AIDS, cancer, sickle cell disease, cystic fibrosis, organ transplant, liver failure or respiratory failure were excluded from the study.

Case subjects were defined using a primary composite endpoint of nonfatal MI, nonfatal stroke, or death attributed to cardiovascular causes (MI, stroke, heart failure or arrhythmia) between January 2005 and December of 2007. The date of the case-defining event as listed as the index date. Control subjects without the primary endpoint during the time window were eligible for matching. Each case subject was matched with four control subjects based upon age and sex. Control subjects were assigned to a pseudo-event date equal to the index date of their matched case subject. Patients without a continuous three year membership and drug benefits with KPSC prior to the index date, patients whose first type 2 diabetes diagnosis occurred after their index date and patients with no recorded A1c in the observational window were excluded.

Case and control subjects were assigned to A1C categories based upon their average A1C measured over 3 years prior to the index date. Sensitivity analyses were performed using their median A1C and most recent A1C prior to the index date. The study’s A1C categories are consistent with the ACCORD study (≤6%, >6%-8% [comparison group] and >8%).

Concurrent diabetes medications were categorized into six commonly prescribed regimens within KPSC: insulin monotherapy; metformin monotherapy; sulfonyurea monotherapy; insulin plus oral medications; other oral medications or combinations; and no diabetes medications. Medication adherence with diabetic drugs was measured using the proportion of days covered over the year prior to the index. Dichotomous variables also were defined to reflect the use of statins, ACE inhibitors, angiotension receptor blockers (ARBs), other antihypertensives, antiplatelets, first-and-second generation antipsychotics, antiarrhythmics, tricyclic antidepressants, erythroprotein-stimulating agents (ESAs) and β-agonists.   

Dichotomous variables were created to reflect cardiovascular events during the three year preindex period, including hospitalizations for MI, stroke, heart failure, or arrhythmia. Outpatient cardiovascular diagnosis included hypertension, peripheral vascular disease or heart failure. Diagnoses of retinopathy, nephropathy, chronic kidney disease, neuropathy and prior amputations suggesting microvascular disease were included in the covariates. Finally, severe episodes of hypoglycemia or hospitalizations were captured using dichotomous variables.

Conclusions - In this study, patients with type 2 diabetes who achieved mean A1C levels ≤6% or who failed to decreased their A1C levels to <8% over a three year period were at increased risk for cardiovascular events compared with patients with mean A1C levels between >6% and 8%. Although treatment effects varied across subgroups with different risk profiles, these subgroup analyses are consistent with the core results.

These results are consistent with the ACCORD trial, which found a significant increase all-cause death and cardiovascular death in the intensively treated arm. The study also lends support to the results of a recent retrospective cohort study by Currie et al. which found a U-shaped association between survival and A1C in this study, patients with the lowest A1C levels (median 6.4%) were at a 52% risk of all-cause mortality relative to patients with a median A1C of 7.5%. In addition, patients in the highest A1C group (mean A1C 10.5%) were at a 79% increased relative risk. However, the results differ from that of the UK Prospective Diabetes Study (UKPDS) 10-year follow-up, which demonstrated that intensive treatment was associated with a 15% relative risk reduction in MI.

The findings suggest that with respect to A1C control, aggressive lowering may not be appropriate for all type 2 diabetic patients. Although the potential for bias precludes casual conclusions from being drawn about the relationship between mean A1C and cardiovascular risk, the findings along with the ACCORD trial and the study by Currie et al. have implications for clinical practice. Whereas uncontrolled hyperglycemia is an established risk factor for microvascular disease, intensive A1C control may not be the best approach for all type 2 diabetic patients. Initiation of intensive glycemic control warrants careful consideration of individual cardiovascular risk profiles. For a given individual, aggressive treatment strategies should carefully weigh the benefit of preventing microvascular complications with the risk of precipitating cardiovascular events. Further research is needed to identify the types of patients for whom intensive glycemic control would be most appropriate medication regimes. Ultimately, mitigating cardiovascular risk requires a miltifactorial approach, glycemic control coupled with lipid lowering and blood pressure control, as well as lifestyle interventions.       

Reprinted with permission from the American Diabetes Association

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