Glycemic Control Targets and Cardiovascular Events in Patients with Type 2 Diabetes: The Answer Remains Elusive

Cardiovascular disease (CVD) is the main cause of death and disability in patients with type 2 diabetes.[1] Given the fact that hyperglycemia is the chief manifestation of diabetes, and due to known detrimental effects of elevated glucose on the vascular wall, [1] the hypothesis that lowering glucose can prevent further vascular wall damage and reduce CVD events is certainly a logical one and has inherent “face validity.” Moreover, this hypothesis was supported by several large observational studies, [2,3] showing an association between better glucose control [as manifested by lower hemoglobin (Hb) A1C levels] and lower risk of CVD events, as well as a non-significant reduction in the risk of CVD events seen in prior randomized clinical trials of intensive versus standard glucose control, such as United Kingdom Prospective Diabetes Study (UKPDS).[4] Nevertheless, this hypothesis still required definitive testing in large scale, randomized clinical trials. Three such trials have been recently published, including Action to Control Cardiovascular Risk in Diabetes (ACCORD), [5] the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) [6], and The VA Diabetes Trial (VADT); [7] and in none of these studies did intensive glucose control result in significant CVD event reduction. Given these results, a careful re-examination of the clinical guidelines and recommendations was needed. In this issue of Circulation, the joint statement from the American Diabetes Association, American College of Cardiology, and the American Heart Association provides an excellent summary of these randomized trials and offers guidance on how the results of these studies should apply to the clinical practice.

The joint statement makes several critically important points, which have direct impact on future research directions and clinical practice. First, it stresses the importance of performing large randomized clinical trials as the main vehicles of hypothesis testing in clinical care. There have been numerous prior instances when clinical trials have failed to confirm hypotheses generated from observational research and physiologic studies, including hormone replacement therapy for CVD prevention, [8] torcetrapib to raise HDL, [9] and others. Similar to these previous examples, glucose-lowering interventions failed to reduce macrovascular events (such as cardiovascular death and myocardial infarction) despite their substantial positive impact on the surrogate endpoint (i.e., Hb A1C). Aside from any potential consequences these studies may have on clinical management of patients with type 2 diabetes, their findings serve as an important reminder that large clinical trials that use clinically meaningful endpoints need to be conducted to prove the value of even such obvious interventions as glucose lowering in type 2 diabetes.

Second, the authors acknowledge that the strength of the evidence in regards to the value of strict glucose control in improving patient outcomes is clearly different for micro- and macrovascular disease events. The evidence that intensive glucose control reduces the progression of microvascular disease in patients with type 2 diabetes continues to be relatively uniform to date and has been reinforced by the ADVANCE study, which showed lower incidence of nephropathy in the intensive glucose control group.[6] Reducing microvascular disease complications continues to be important, with significant impact on patients’ quality of life. Therefore, an Hb A1C of <7% remains a reasonable goal for the purpose of microvascular disease prevention.

What Hb A1C target is optimal for the prevention of CVD events in patients with type 2 diabetes? The honest answer is that we simply do not know. The findings from the ACCORD, ADVANCE, and VADT demonstrate that aggressive Hb A1C lowering to near-normal levels in patients with type 2 diabetes is not beneficial for the prevention of CVD events in general, [5-7] and may even be harmful in some patient populations.[5] Yet, long-term epidemiologic follow-up data from UKPDS [10] and subgroup analyses from the ACCORD and VADT studies also suggest that long-term intensive glucose control (Hb A1C level of below or approximately 7%) may reduce CVD events in patients who are newly diagnosed or have short duration of type 2 diabetes, and no preexisting vascular disease.[5,7] Until future clinical studies provide more definitive data in regards to Hb A1C targets across various patient subgroups, the optimal glycemic control goals for CVD prevention in patients with type 2 diabetes remain unclear.

Given this uncertainty, what strategy should clinicians use today when trying to provide optimal glucose control to patients with type 2 diabetes? Although the statement suggests that the general Hb A1C target of <7% should not be abandoned by clinicians, it strongly stresses that individualized approach to glucose control is most appropriate. Because the majority of glucose-lowering interventions (with the likely exception of lifestyle modifications) are not risk-free, a risk-benefit analysis should take place on the individual patient level. More aggressive Hb A1C goals may be appropriate in patients who have been recently diagnosed or have short duration of diabetes, and no established vascular disease, as well as no history of severe hypoglycemia. Conversely, the risk of intensive glucose control may outweigh its benefits in patients with advanced diabetes, particularly those with diffuse atherosclerotic vascular disease, severe hypoglycemia, as well as those who are frail and have limited life expectancy. Clearly, a discussion of potential benefits and risks, as well as individual patient preferences should guide clinical decisions regarding the aggressiveness of glucose lowering. In addition, these discussions will provide another opportunity to stress the importance of evidence-based approaches proven to reduce CVD events, such as blood pressure control and lipid lowering with statins, as outlined in the statement.

Finally, it is important to point out that ACCORD, ADVANCE and VADT studies concentrated on comparing more aggressive versus less aggressive glucose lowering. The fundamental assumption used in all three trials was that Hb A1C lowering has similar impact on CVD events regardless of the specific strategies used. Whether this assumption is correct remains to be established. Various strategies that employ different glucose-lowering pharmacotherapeutics or combinations of drugs and lifestyle changes may have different impact on CVD outcomes. Indeed, it is possible that specific strategies used for glucose control may be as important as the Hb A1C levels themselves. Testing the comparative effectiveness and safety of various glucose lowering interventions represents the next logical and critically important phase in our understanding of glycemic control and CVD outcomes in patients with type 2 diabetes.