Is aspirin’s benefit for MI and CVA amplified in diabetes patients? Multiple clinical trials have confirmed the benefits of aspirin for secondary prevention of cardiovascular events and mortality for both men and women.18 The average RRR seen in clinical trials of aspirin has been between 15% and 18%.19 Relative risk reductions predicted by Archimedes were approximately twice that (30%-35%, data not shown). We have no explanation for this other than that all of the patients analyzed had diabetes mellitus, and so were different from most patients included in the clinical trials.
Aerobic exercise reduces the risk of fatal MIs. Studies examining the cardiovascular benefits of aerobic exercise have looked primarily at intermediate outcomes, such as reductions in BP or lipid levels and improved endothelium-dependent vasodilatation.20,21
The effect of aerobic exercise on risk of cardiovascular events has primarily been investigated in the context of cardiac rehabilitation programs, which also offer other forms of lifestyle counseling and tend to include patients who have already suffered a cardiac event. In a meta-analysis of 48 clinical trials, Taylor et al found that cardiac rehabilitation programs reduced all-cause mortality and cardiac mortality, but they found no difference in the rates of nonfatal MI or need for revascularization.22 Two other meta-analyses have documented that such programs significantly reduce fatal reinfarction rates, sudden deaths, and overall mortality, but not nonfatal reinfarctions.23,24
LDL reduction’s surprisingly negligible effect on risk of stroke. An overview of lipid-lowering trials conducted before 1995 found that reducing LDL levels by 22% to 30% decreased the incidence of strokes by 29%.25 A separate systematic review conducted by Crouse et al concluded that, in patients with coronary artery disease, statin therapy reduced risk of stroke by 27%.26 Again, the initial LDL level for our cases was only 120 mg/dL, so a 25% reduction would have lowered it to 90 mg/dL, and an RRR of 29% would have resulted in an ARR of 4% in the base case. Our simulated reduction of LDL to 70 mg/dL yielded an ARR of just 0.4%. However, our cases did not have a history of coronary artery disease, which makes them very different from the participants in most of the clinical trials.
HbA1c control is important for MI and CVA prevention. Controlling hyperglycemia was the most effective way to lower risk of foot ulceration. It was also quite effective at reducing risk of MI and CVA—comparable to, or better than, BP and LDL control. However, the HbA1c for the base case was 10%, so our intervention (3% reduction) was more substantial than in most clinical trials. Though early clinical trials were unable to demonstrate an effect of HbA1c control on macrovascular outcomes, except when metformin was used, newer trials are confirming a benefit of glycemic control on macrovascular disease and events.27 Interestingly, Archimedes predicted that very tight control of HbA1c to 6.5%, BP to 120/80 mm Hg, and LDL to 70 mg/dL would be substantially more effective than control to standard targets.
Unanticipated lack of effect with ACE inhibitors. Another surprising finding of this study was that using ACE inhibitors had no effect on risk of MI or CVA. This is inconsistent with the literature, which has shown that ACE inhibitors significantly reduce all-cause mortality, cardiovascular mortality, nonfatal MI, strokes, and need for revascularization in patients at high risk for these events.28-30
Reduction of BMI alone had no effect on risk of adverse events. However, in these simulations the BMI was not very high to begin with.
Clinical recommendations. Though we did our best to choose cases that physicians would consider typical, each patient with diabetes will have a unique clinical profile. Patients with clinical profiles similar to our cases would probably benefit more from aspirin and moderate exercise than from all other interventions combined.
The Archimedes diabetes risk engine is a well-validated tool that can be used to enhance shared decision-making in primary care settings, though for some interventions it seems to be in conflict with the results of clinical trials.
Correspondence
James W. Mold, MD, OUHSC Department of Family and Preventive Medicine, 900 NE 10th Street, Oklahoma City, OK 73104; james-mold@ouhsc.edu