Based on relatively novel analysis, we have answered two important questions: 1) A1C needs to be lowered to <6.2% to reduce the incidence rate of ischemic stroke substantially and 2) there is biological interaction between A1C ≥6.2% and albuminuria; put in another way, these two risk factors interact to substantially increase ischemic stroke risk in type 2 diabetes, an effect that is more than summation. Based on these findings, we infer that stroke risk can be substantially reduced by lowering A1C to <6.2% or by substantially reducing albuminuria if A1C cannot be reduced effectively and safely to <6.2%.
A meta-analysis of cohort studies showed that every 1% increase in A1C was associated with a 1.17-fold risk of stroke (1
). We have reported a 1.49-fold increased risk of ischemic stroke per 1% increase in A1C in Chinese patients with type 2 diabetes (20
). These increased risks may be attributable to the high prevalence of albuminuria in our population—estimated at 50–60%—that has also been reported in other Asian populations (21
). In the landmark DCCT involving 1,441 patients with type 1 diabetes followed up for 17 years (3
), microalbuminuria was more prevalent (13 vs. 7%, P
< 0.01) and A1C was higher (9.1 vs. 7.4%, P
< 0.01) in the conventional treatment group than the intensive insulin treatment group, with the latter conferring 42% risk reduction in any cardiovascular events. In the UKPDS, which consists of 3,867 newly diagnosed type 2 diabetes patients followed up for 10 years (22
), a 0.9% difference in achieved A1C between the intensive and conventional treatment groups was associated with nonsignificantly higher stroke risk (relative risk 1.11, P
= 0.52). Our findings may provide an explanation for these discrepant findings between type 1 and type 2 diabetes. In the UKPDS, over a 10-year period, A1C in the intensive treatment group was significantly lower than that in the conventional treatment group (P
< 0.0001). However, A1C level in the intensive treatment remained high (median: 7%, interquartile range: 6.2–8.2%). Given the near-linear relationship between A1C and stroke rate and that many type 2 diabetic patients may have coexisting albuminuria, it is conceivable that the interactive effects of suboptimal glycemic control and albuminuria may explain the failure to reduce the stroke rate.
Given the powerful risk associations between microalbuminuria and cardiovascular complications in type 2 diabetes and the lack of effective therapy to reduce hyperglycemia without causing hypoglycemia, our data strongly support the aggressive reduction of albuminuria to compensate for our inability to reduce A1C to <6.2% safely. To this end, we further confirm that albuminuria is a marker of multiple risk factors, especially remediable risk factors, including hypertension, hyperglycemia, high BMI, and high LDL cholesterol. Our findings are particularly intriguing, since in the ADVANCE (Preterax and Diamicron Modified Release Controlled Evaluation) study, the use of the ACE inhibitor perindopril in the intensive treatment arm based on gliclazide and other sulfonylureas, aiming at a target of ≤6.5%, may have enhanced the vasculoprotective effect of glycemic control by reducing albuminuria (23
). The Heart Outcomes Prevention Evaluation (HOPE) study (24
) also reported that ramipril, an ACE inhibitor, helped lower the risk of stroke by 33%, cardiovascular death by 37%, and total mortality by 24%, an effect beyond that due to a decrease in blood pressure. Of note, in the HOPE study, ramipril treatment led to a lower ACR at 1 year and 4 years of study.
Our study has several limitations. First, the cutoff points of A1C, 6.2 and 8.0%, were chosen based on visual observation of characteristics of the hazard ratio curve of A1C for ischemic stroke. Second, only one measurement of ACR and A1C was available for this analysis. Third, this cohort was a clinic-based rather than population-based cohort. However, Hong Kong does not have a comprehensive health insurance policy and integrated primary health care system. Thus, the majority of patients with chronic illnesses are managed in public hospitals more for financial reasons than disease severity. In Hong Kong, 90% of patients diagnosed with diabetes were treated in the public health sector (12
). An annualized rate of 16.43 per 1,000 person-years for mortality and 14.08 per 1,000 person-years for incident CHD in the cohort were similar to those reported in other community-based databases (12
). Fourth, a small number of ischemic events might not have been identified, notably due to emigration to other countries. However, this number is likely to be few, since lack of insurance coverage is likely to reduce the likelihood of emigration or acceptance of these high-risk patients by other countries as permanent residents. Fifth, only baseline measurements of risk factors such as A1C, ACR, lipids, and drug use were available for the present analysis. Metabolic profile may deteriorate over time and, as a result, drug use may increase substantially during the long follow-up period. Sixth, we did not have information on atrial fibrillation or inflammatory or immunological disorder conditions. However, use of antiarrhythmic drugs, glucocorticoids, and nonsteroidal anti-inflammatory drugs in the cohort was very low and not significant for ischemic stroke. Thus, these medical conditions may not have major impacts on the findings of the study.
In conclusion, based on a large prospective cohort of patients with type 2 diabetes, we confirmed the marked increase in the risk of ischemic stroke when A1C ≥6.2% and albuminuria coexist. These findings have important therapeutic implications given our current armamentarium in lowering blood glucose. Until safe and effective agents become available to lower A1C to <6.2%, reducing albuminuria by aggressive control of multiple risk factors, notably blood pressure and inhibition of the renin-angiotensin system, is of critical importance to reduce the risk of stroke in type 2 diabetes.