Diabetes management: More than just cardiovascular risk?
CARDIOVASCULAR RISK, HYPOGLYCEMIA, AND ATTAINING GLYCEMIC TARGETS
Metformin, in the absence of contraindications or intolerability, is generally the recommended first-line therapy to manage glycemia in patients with type 2 diabetes mellitus.10,11 However, there are only limited data to direct clinicians as to which antidiabetic medication to use if further therapy is required to obtain glycemic control.
Much of the cardiovascular and mortality risk associated with aggressive diabetes management (ie, lower A1c targets) is related to hypoglycemia. Thus, antidiabetic therapies that pose no risk or only a low risk of hypoglycemia should be chosen, particularly in older patients and in those with known cardiovascular disease. This may allow for better glycemic control without the risk of hypoglycemia and adverse cardiovascular outcomes.
However, in practice, clinicians continue to use a sulfonylurea as the second-line agent. Although sulfonylureas may appear to be a great option because of their low cost, they are associated with a higher risk of hypoglycemic episodes than other classes of diabetes drugs. We need to consider the frequency and cost of hypoglycemic episodes and the potential morbidity associated with them, because these episodes are a barrier to our efforts to achieve better glycemic control.
Budnitz et al12 reported that from 2007 through 2009, in US adults age 65 and older, insulins were implicated in 13.9% of hospitalizations related to adverse drug events, and oral hypoglycemic agents (ie, insulin secretagogues) in 10.7%.
Quilliam et al13 reported that hypoglycemia resulted in a mean cost of $17,564 for an inpatient admission, $1,387 for an emergency department visit, and $394 for an outpatient visit. Thus, the cost savings associated with prescribing a sulfonylurea vs one of the newer oral antidiabetic agents that do not increase the risk of hypoglycemia (unless used concurrently with insulin or an insulin secretagogue) can quickly be eroded by severe hypoglycemic episodes requiring medical care.
Moreover, once patients start to experience hypoglycemic episodes, they are very reluctant, as are their physicians, to intensify therapy, even if it is indicated by their elevated A1c.
There are now seven classes of oral antidiabetic therapies other than insulin secretagogues (ie, other than sulfonylureas and the meglitinides nateglinide and repaglinide), as well as a few noninsulin injectable therapies (glucagon-like peptide-1 agonists), that are not associated with hypoglycemia. We believe these agents should be tried before prescribing an agent that carries the risk of hypoglycemia (ie, sulfonylureas).
If agents that do not cause hypoglycemia are used, more-aggressive glycemic targets may be achieved safely. The ACCORD study,2 which included patients at high cardiovascular risk and aimed at an aggressive glycemic target of 6%, may have yielded much different results had agents that carry a high risk of hypoglycemia been excluded.
Of importance, cardiovascular risk is also influenced by the common comorbidities seen in patients with diabetes, such as hypertension and hypercholesterolemia. Intensive, multifactorial interventions that address not only glycemic control but also blood pressure and lipids and that include low-dose aspirin therapy have been shown to lower the risk of death from cardiovascular causes and the risk of cardiovascular events.14 Likewise, smoking cessation is very important in reducing cardiovascular risk, especially in patients with diabetes.15
CLINICAL TRIALS IN CONTEXT
In conclusion, there is more to diabetes management than cardiovascular complications. Clearly, improved glycemic control decreases the risk of retinopathy, nephropathy, and neuropathy in patients with type 1 and type 2 diabetes. The DCCT and UKPDS extension studies further found that excellent glycemic control decreases rates of cardiac events.
The best way to treat diabetes may be different in otherwise healthy younger patients who have yet to develop significant complications than it is in older patients known to have cardiovascular disease or several risk factors for cardiovascular events. The available evidence suggests it would be reasonable to aim for stricter glycemic targets in the younger patients and less stringent targets in the older patients, particularly in those with long-standing diabetes who have already developed significant micro- and macrovascular complications.
We should interpret clinical trials within their narrow clinical context, emphasizing the actual population of patients included in the study, so as to avoid the inappropriate extrapolation of the results to all.
