Take-aways Glucose control has been thought to be the cornerstone of preventing vascular outcomes in patients with diabetes. Studies, however, show little benefit of glucose control on cardiovascular endpoints and, indeed, there is some evidence of harm with this approach. Glucose control may still be valid for preventing microvascular disease but there is probably more uncertainty today than ever in terms of the role for glucose control in the prevention of atherosclerotic vascular disease.

The association between diabetes mellitus (DM) and CVD is profound: CVD accounts for approximately 80% of death in people with either type 1 or type 2 DM¹ and the presence of DM increases CVD risk 2- to 4-fold.² Due to this intensive interplay, DM is considered a CVD risk equivalent when developing risk reduction strategies.

In 2010, glycated hemoglobin or HbA1C was officially adopted by the American Diabetes Association (ADA) as a criterion for determining diabetes status. Hemoglobin in red blood cells sometimes joins with glucose in the bloodstream and the A1C test indicates the average blood glucose level over the previous 2–3 months. An individual with an A1C of ≥6.5% would be diagnosed with DM, while an A1C 5.7–6.4% is considered prediabetes.³ However, the ADA considers achievement of a target A1C<7.0% as well-controlled diabetes, but recognizes that stringent goals may be appropriate for certain patients.

How Low Can You Go?

Larger-scale trials did not show similar risk reduction in terms of “macrovascular” CVD outcomes based on comparisons between intensive and standard glycemic control. Neither the Action in Diabetes and Vascular Disease—Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) or the Veterans Affairs Diabetes Trial (VADT) showed significant reduction in cardiovascular outcomes with intensive glycemic control. It was even worse in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, which terminated its glycemic control study early due to increased mortality in the intensive glycemic control arm.²

Since then, the news has not gotten any better, and aggressive therapy continues to disappoint. Following yet more bad news presented at ESC.13, Barbara Casadei, MD, University of Oxford, United Kingdom, said, “We target specific glycated hemoglobin levels with the expectation that this will always influence macrovascular complications, but that is not happening and there is a suggestion that there is harm.”

That suggestion was a signal of increased HF in SAVOR-TIMI 53, which was presented at the ESC Congress in Amsterdam.⁴ Investigators randomized patients to a selective dipeptidyl peptidase 4 (DPP-4) inhibitor or placebo. Active therapy was associated with better control of glucose versus placebo, with absolutely no effect on the primary composite endpoint of MI, stroke, or cardiovascular death. However, there was an increase in hospitalization for HF in the DPP-4 arm.

Refocus Therapy in Patients with Diabetes

During a broadcast of ESC 2013 highlights, Keith A.A. Fox, MD, University of Edinburgh, United Kingdom, and Dr. Casadei agreed that, based on the evidence, no one should consider glycated hemoglobin a good biomarker of macrovascular complications. Sanjay Sharma, MD, added that good glycemic control benefits microvascular disease but not macrovascular disease. Consequently, he said, “We need to ease off on the ‘sweet spot’ for glycated hemoglobin and focus more on other risk factors for atherosclerosis; because in high-risk individuals, there is evidence that long-acting insulins have precipitated MI and now the glitazones and gliptins have been associated with heart failure.”

It should be noted that SAVOR-TIMI 53 is the largest diabetes trial ever carried out, conducted at 788 sites across 26 countries. It is also the first study since the US FDA and the European Medicines Agency revised regulations to give more robust assurance of cardiovascular safety in glucose-lowering therapies following concerns that these drugs may have substantial deleterious effects.

Overall, Dr. Sharma suggests less emphasis on hard and fast targets of glucose and more attention to the metabolic syndrome; this means more global risk reduction as well as pushing harder to get patients to increase activity to improve their metabolic profile. Even just a brisk 1-hour weekly walk would significantly reduce CVD risk as well as all-cause mortality, he said: “For every MET [metabolic equivalent] increase in exercise you reduce your cardiovascular risk by 13%. That makes it more powerful than statins or any other intervention you can name—and it’s free.”

Darren K. McGuire, MD, agrees: “As we have all seen as the last couple decade’s worth of data have emerged, diabetes is much more than hyperglycemia.” From a cardiologist’s perspective, he said, it’s important to utilize optimal medical therapy to reduce the general cardiovascular risk in patients with diabetes, including statin therapy, angiotensin-converting enzyme inhibitors, antiplatelet therapies, and other approaches known to improve outcomes.

We assumed forever that glucose control was a focus for type 2 diabetes, said Dr. McGuire, and glucose control may still be valid for preventing microvascular disease. However, he said, “We’re probably more uncertain presently than we have ever been in terms of the roll of glucose control in terms of the prevention of atherosclerotic vascular disease.”

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References

1. Buse JB, et al. Circulation. 2007;115:114-26.
2. Skyler JS, et al. J Am Coll Cardiol. 2009;53:298-304. http://content.onlinejacc.org/cgi/content/full/53/3/298
3. American Diabetes Association. Standards of medical care in diabetes--2012. Diabetes Care. 2012;35 Suppl 1:S11-63.
4. Scirica BM, et al. N Engl J Med. 2013;369:1317-26.

To listen to an interview with Darren K. McGuire, MD, about glycemic control in CVD, visit youtube.cswnews.org. The interview was conducted by Stephen D. Wiviott, MD.

Keywords: Glycated Hemoglobin A, Stroke, Atherosclerosis, Insulin, Long-Acting, Risk Reduction Behavior, Blood Glucose, Diabetes Mellitus, Type 2, Heart Failure, Cardiovascular Diseases, Risk Factors, Glucose

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