We have an unsatisfactory state of affairs regarding thrombotic management in diabetes patients. We know that there's a strong relationship between inflammation and thrombosis, and as diabetes progresses, that risk is enhanced, leading to increased risk of obstructive coronary artery disease and stroke. The treatments that we have don't seem to be working, and there doesn't seem to be a one-size-fits-all medication.
Options for the treatment of thrombotic risk in diabetes are limited. There are three ways that we can look at this.
The first is by taking a general view of how we can improve glycemic control, and a variety of pleiotropic things that might benefit thrombosis. There's evidence that lipid-lowering agents and some specific diabetes treatments have beneficial effects on inflammatory and thrombotic processes. If we improve glycemic control, that benefits elements of all these processes.
Second, we can try to generate drugs that are specifically designed to treat these problems. The peroxisome proliferator–activated receptor (PPAR)–gamma agonists (such as rosiglitazone) are a model of this process. They have several effects, all of which should be beneficial in relation to both thrombosis and heart disease in general.
Third, we can target the specific pathways that are involved in thrombosis. Antiplatelet therapies are one example. Let's look at aspirin.
A meta-analysis by the Antithrombotic Trialists' Collaboration (Lancet 2009;373:1849-60) examined 6 primary prevention trials (95,000 subjects at low average risk who were treated for 660,000 person-years) and 16 secondary prevention trials (17,000 people at high average risk who were treated for 43,000 person-years). In primary prevention, aspirin did not seem to have any effect on mortality but it did significantly increase major gastrointestinal and extracranial bleeds. Most people would now say we shouldn't be giving aspirin to healthy people with uncomplicated diabetes for primary prevention because of the increase in major bleeds.
But for secondary prevention, aspirin in this huge analysis provided a 23% reduction in total events and nearly a 20% reduction in stroke—a major statistical advantage.
My associates and I looked at the effects of aspirin in a separate study of 2,499 patients with acute coronary syndrome, 425 of whom had diabetes (Diabetes Care 2008;31:363-5). We found a major reduction in mortality in nondiabetic subjects and no mortality effect in diabetic subjects, leading us to wonder about the precise role of aspirin in diabetes.
The results of a separate study of aspirin use in 58,465 Swedish patients with diabetes are especially worrisome, particularly when you consider it alongside the Antithrombotic Trialists' Collaboration data set. In the Swedish study, aspirin use increased mortality in diabetes patients without cardiovascular disease by 17% at age 50 and by up to 29% at age 85 years (Pharmacoepidemiol. Drug Saf. 2009;18:1143-9). Aspirin increased the risk of serious bleeding in patients without cardiovascular disease by 46%. In contrast, aspirin tended to decrease mortality and the risk of serious bleeds in elderly diabetes patients with cardiovascular disease.
In Europe, the view is developing that aspirin should be used with caution in primary prevention in type 2 diabetes.
Clopidogrel, another antiplatelet drug that acts differently from aspirin, was shown to be beneficial in the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study (Lancet 1996;348:1329-39). A substudy of the 3,866 patients in this cohort who had diabetes confirmed that clopidogrel was better than aspirin for secondary prevention.
In diabetes patients, clopidogrel probably should be used as primary prevention only in those with a very high risk for ischemic events.
Dual antiplatelet therapy in primary prevention is not recommended. The combination of aspirin and clopidogrel is widely used, however, in patients with unstable angina or non–ST-elevation myocardial infarction.
The Food and Drug Administration, the American College of Cardiology, and the American Heart Association all recommend clopidogrel in patients with ST-elevation myocardial infarction as well. The recommendations are that it should be used in acute coronary syndrome and continued for 1 year.
For the new kid on the block—prasugrel—there has been one study that included patients with diabetes and acute coronary syndrome (N. Engl. J. Med. 2007;357:2001-15). In the overall cohort of 13,608 patients, prasugrel lowered the rate of ischemic events, increased major bleeding, and made no difference in mortality. In the diabetes subgroup, however, prasugrel was associated with a 30% reduction in ischemic events, but it still didn't bring risk down to that of the nondiabetic population.
Novel anticoagulants and antiplatelet therapies are being developed. And an area that is open to investigation in diabetes is inflammation therapeutics, which is aimed at linking our understanding of inflammation with the treatment of thrombotic risk and vascular disease progression.