Rationale for glycemic control to improve cardiovascular outcome: Lessons from east and west

Abstract

It is clear that there is a strong relationship between diabetes and cardiovascular disease (CVD). Both for men and for women, diabetes confers the highest lifetime risk for coronary arterial disease (CAD) as a single independent risk factor. In a metaanalysis of 102 prospective studies of more than 500 000 persons, there was a doubling of risk both of CAD and stroke associated with diabetes, adjusted for age, cigarette use, obesity, hypertension, and sex. Further analysis from this group of a larger cohort of nearly 700 000 persons showed that diabetes, a history of myocardial infarction (MI), and a history of stroke were associated with similar mortality. The presence of any two of these factors led to a doubling of risk, and the presence of all three to a doubling again for mortality risk. Although the Swedish National Diabetes Register showed progressive reduction in CVD from 1998 through 2014 among persons both with and without diabetes, the gap in CVD death and hospitalization rates between the groups persisted throughout the period. Diabetes is characterized by persistent elevation in blood glucose levels. As such, it is reasonable to postulate that greater glycemic exposure is associated with greater levels of risk of complications. Indeed, in a cohort of persons representative of the US population varying from euglycemia to prediabetes to diabetes with progressively higher HbA1c levels followed from 1998 through 2011, CVD mortality increased by 25% with HbA1c 8%-8.9% compared with HbA1c of 7%-8% and by another 25% with HbA1c of 9% or more. In the Swedish National Diabetes Register diabetes cohort of more than 250 000 persons, mortality, MI, stroke, and heart failure increased progressively with rising HbA1c with marked increase as HbA1c rose from 7% to 9%. In a further study by this group using an expanded cohort of more than 400 000 persons with diabetes, over a 7-year period, the stroke rates in persons with HbA1c 7.1%-8%, 8.1%-9%, 9.1%-10%, and >10% were 1.27-, 1.68-, 1.89-, and 2.14-fold greater than that in matched persons without diabetes. Is there then evidence from trials showing that CVD outcomes improve with glycemic control in persons with diabetes? The evidence here is complex. In a metaanalysis of trials of 3-6-year duration of persons with diabetes and underlying CVD or CVD risk factors, there was significant reduction in rates of MI but not for stroke and mortality. However, in persons receiving more vs less intensive glycemic treatment beginning earlier in the course of diabetes, there was a legacy effect after 10-20 years of follow-up with reduction in MI, mortality, and CVD rates both in type 2 and in type 1 diabetes. In an analysis of the Veterans Administration Diabetes Trial comparing more vs less intensive glycemic control where participants were divided by the presence of CVD based on coronary artery calcium (CAC) measurement, those with negative scores (CAC score ≤ 100) showed lower rates of CVD but not those with positive CAC scores. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial where higher mortality rates were reported with intensive glycemic treatment, the increase in mortality occurred only in participants with higher baseline HbA1c or higher mean on-trial HbA1c. Taken together, these trials evidence suggested that the CV benefits of intensive glycemic treatment, while minimizing risk of hypoglycemia, were most evident when implemented early, and certainly before development of atherosclerotic cardiovascular disease. In contrast, for those with higher HbA1c and long disease duration, intensive glycemic treatment, particularly with agents associated with high risk of hypoglycemia, might not show benefit (Figure 1). Indeed, in the ACCORD trial and similar studies, severe hypoglycemia was a particularly significant mortality risk factor. These observations may be particularly important in people who develop type 2 diabetes at younger age and face many decades of hyperglycemia. In the Hong Kong Diabetes Register, total hyperglycemic exposure is more than 3-fold greater in patients diagnosed before the age of 40, who had 3-6-fold higher risks of CVD, kidney disease, and infections compared with those diagnosed after the age of 40. In these young patients, it was estimated that intensive control of all cardiometabolic risk factors to near normal targets as evaluated in the J-DOIT3 (Japan Diabetes Optimal Integrated Treatment study for three DOI: 10.1111/1753-0407.13204