Comprehensive diabetes cardiovascular treatment = sugar + blood pressure + lipids

doi: 10.1111/j.1753-0407.2011.00161.x

Journal of Diabetes 3 (2011) 257–260

EDITORIAL

Comprehensive diabetes cardiovascular treatment = sugar + blood pressure + lipids

The approach to the treatment of patients with diabetes must be comprehensive and must combine control of glycemia, blood pressure, and lipids for optimal cardiovascular (CV) protection. The recent International Diabetes Federation (IDF) estimate is that 366 million people worldwide have diabetes;1 a higher number have abnormal glucose tolerance and are at risk of developing diabetes, with CV risk increasing as the degree of dysglycemia worsens.2 Yet, despite the IDF estimate that, somewhere in the world, every 7 s a person dies of diabetes, hyperglycemia is often ignored as a CV risk factor. A Perspective appearing in a recent issue of the New England Journal of Medicine discussing reduction in myocardial infarction and stroke focuses on aspirin, treatment of blood pressure and lipids, and cessation of smoking and, while acknowledging that lifestyle has a role in the prevention of diabetes, emphasizes primarily a reduction in dietary sodium and trans-fats as approaches to reducing CV disease (CVD) in the general population.3 Such a concept is particularly worrisome in that the authors of the Perspective are the Director of the Centers for Disease Control and Prevention and the Administrator of the Centers for Medicare and Medicaid Services, playing crucial roles in decision making about healthcare efforts in the US. A great deal of accumulated evidence, outlined below, suggests that controlling hyperglycemia improves CV outcomes. Glucose At the end of the United Kingdom Prospective Diabetes Study (UKPDS) and at 10-year follow-up, after glucose levels had become equivalent in the intervention and control groups, diabetes-related endpoints were significantly decreased by 12% and 9%, and microvascular endpoints by 25% and 24%, respectively.4 At study end, the 16% reduction in myocardial infarction was not statistically significant but, at 10-year follow-up, there was a significant 15% reduction,

suggesting that the initial decline had been biologically meaningful. Similarly, all-cause mortality was not significantly reduced at study end, but showed a significant 13% reduction at the 10-year post-trial follow-up. The same pattern of a non-significant reduction in CVD at study end but a significant 42% reduction at 8-year post-trial follow-up was seen in the Diabetes Control and Complications Study (DCCT).5 Thus, the evidence of microvascular benefit in these trials at the end of the study appeared subsequently to be extendable to a reduction in macrovascular events. There has been concern because of the significant 24% increase in mortality in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial in type 2 diabetic patients assigned to be controlled to a mean A1c of 6.4% rather than 7.5%,6 as well as with the non-significant increase in mortality (by 36%) in the Veteran’s Administration Diabetes Trial (VADT) in type 2 diabetic patients controlled to a mean A1c of 6.9% rather than 8.4%.7 However, it is of note that the absolute hypoglycemia rate was threefold higher among those having more intensive glycemic treatment and that in both studies hypoglycemia was strongly associated with increased mortality. In the ADVANCE trial, with A1c 6.4% vs 7.0%, there was a small, albeit nonsignificant, reduction in mortality and hypoglycemia rates were considerably lower with both treatments,8 although they continued to be significantly associated with mortality. Fascinatingly, among participants in the intensive glucose treatment group in the ACCORD trial, it was not a lower A1c that was associated with higher mortality; rather, it was the patients whose efforts at intensive control failed who had higher mortality. In fact, there was a significant reduction of nearly 10-fold in mortality among the intensive treatment group at an A1c level of 6% and a 10-fold increase in mortality in those who were randomized to intensive treatment but had an A1c of 9%.9 This actually implies that intensive control of glucose, in a manner that did not cause an excess in hypoglycemia, was, in fact, beneficial.

ª 2011 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd

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Editorial

Lipids There is certainly extensive evidence of the benefits of lipid-lowering treatment among diabetic people, including results from the Scandinavian Simvastatin Survival Study, which found that simvastatin reduced CVD and mortality in patients with diabetes, as well as in those with normal and impaired fasting glucose,10 and findings from the Heart Protection Study of a reduction in CVD among diabetic patients,11 to give just two examples of many randomized controlled trials of statin treatment. There is potential for benefit with fibrates as well, with diabetic participants in the Veterans’ Administration HDL Intervention Trial having similar relative and greater absolute CVD reduction than non-diabetic people.12 Fenofibrate was associated with reduction in coronary heart disease and in total CVD events in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.13 It is important to note that the final results of the FIELD study may have not been as robust as expected because of the nearly twofold greater use of statins in the placebo group.13 In the ACCORD Lipid Trial,14 all patients received simvastatin, with either fenofibrate or placebo added; the fenofibrate-treated subgroup with baseline triglyceride >203 mg ⁄ dL and high-density lipoprotein–cholesterol