EXPERT ANALYSIS FROM WCIRDC 2017
LOS ANGELES – If you think the link between glucose control and cardiovascular disease is complicated, you’re not alone.
“Glucose is not the only risk factor for CVD, and it may not be the most important risk factor,” Peter Reaven, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Controlling blood pressure and lipids is also quite important. In current studies, patients with diabetes are aggressively treated for other risk factors with many vascular-acting medications, so it’s difficult to show the benefits of glucose lowering on its own. That is pertinent because it’s becoming clear that the benefits of glucose lowering may take a long time. How, and in whom, one controls glucose may influence the outcome.
Medications, hypoglycemia, glucose variation, and extent of disease all may influence vascular responses to glucose lowering.”
Dr. Reaven, an endocrinologist who directs the Diabetes Research Program at the University of Arizona and VA Health Care System, Phoenix, noted that, while a consistent body of evidence supports an association between higher levels of glucose and increased risk for CVD, it’s not as clear that tight control efforts decrease a patient’s risk for CVD at the microvascular and macrovascular level. “We also appreciate that complications from intensive glucose lowering – such as hypoglycemia, weight gain, time and cost, and increased mortality – are not minimal,” he said.
A meta-analysis of 27,049 patients with type 2 diabetes enrolled in four major trials found that those who were allocated to more-intensive, compared with less-intensive, glucose control had a reduced risk of major cardiovascular events by 9% (hazard ratio, 0.91), primarily because of a 15% reduced risk of myocardial infarction (Diabetologia 2009;52 2288-98). “None of these studies actually achieved statistical significance, but they all showed a modest trend,” said Dr. Reaven, who was not involved in the meta-analysis. At the same time, interim data from the Veterans Affairs Diabetes Trial follow-up study (VADT-F) showed that, after about 10 years, the median HbA1c levels were similar between patients who had received either intensive or standard glucose for a median of 5.6 years in the initial VADT trial (N Engl J Med. 2009;360:129-39). Other risk factors between the two groups were similar, including LDL and systolic and diastolic blood pressures.
In this extended follow-up of the VADT, a 17% reduction in CVD was observed among patients who were treated more intensively, compared with those on standard therapy, after about 12 years of treatment (P = .04; N Engl J Med. 2015;372:2197-206). “Why does it take so long?” he asked. “Why does it take 10-plus years of mean follow-up with an HbA1c separation of 1.5% to start to lead to cardiovascular events? The reality is, we don’t know the answer.”
It’s possible that many years of hyperglycemia created enough vascular injury and long-term consequences that are not easily turned around in short intervals, but Dr. Reaven noted that advanced glycation and oxidation products might also be contributing to long-term vascular legacy events. In an analysis of patients from the VADT-F, he and his associates found that specific advanced glycation end products and oxidation products are associated with the severity of subclinical atherosclerosis over the long term and may play an important role in the “negative metabolic memory” of macrovascular complications in people with long-standing type 2 diabetes mellitus (Diabetes Care 2017;40:591-8). In particular, the combination of 3-deoxyglucosone hydroimidazolone and glyoxal hydroimidazolone and 2-aminoadipic acid was strongly associated with all measures of subclinical atherosclerosis.
In the initial VADT trial, severe hypoglycemia occurred nearly three times more commonly in the intensively treated group, compared with the standard therapy group. Severe hypoglycemia was defined as an episode of low blood glucose that was accompanied by confusion requiring assistance from another person or loss of consciousness. In related analyses, the hazard ratio for CV events, CV mortality, and overall mortality with severe hypoglycemia within the preceding 3 months was also increased. “So this is a consistent finding across multiple studies of the danger of severe hypoglycemia occurring during your efforts to improve glucose lowering,” Dr. Reaven said. “Interestingly, it appears that the risk for CVD events following severe hypoglycemia increases with higher baseline CV risk, based on the United Kingdom Prospective Diabetes Study 10-year CV risk score. So, how great your risk is begins to influence how well you do after severe hypoglycemia.”
In a separate stratified analysis of VADT data, the risk for CVD after severe hypoglycemia was more prominent in the standard treatment group, compared with the intensive treatment group. “There’s nearly a sevenfold increased risk for all-cause mortality following severe hypoglycemia in the preceding 3 months,” he said. “The same pattern is present for cardiovascular mortality and, somewhat, for cardiovascular events, although not statistically significant. The association between symptomatic, severe hypoglycemia and mortality in type 2 diabetes was seen in the ACCORD [Action to Control Cardiovascular Risk in Diabetes] population as well.”
A subset of patients in the VADT study showed that individuals in the standard therapy group who had a prior serious hypoglycemic episode actually had greater coronary calcium progression during the study, compared with the intensively treated group (P = .02; Diabetes Care 2016;39:448-54). “One possibility is that serious hypoglycemia contributed to the development of atherosclerosis in this group,” Dr. Reaven said. “This held true when one examined high and lower glucose levels on average in the study. Those individuals that had A1c levels of 7.5% or above were the ones that appeared to show coronary calcium progression during the study following episodes of severe hypoglycemia, whereas it did not appear to be an issue among those with good glucose control. Another finding was that severe hypoglycemia is associated with increased glucose variability from office visit to office visit.”
He concluded his remarks by noting that being “glucose centric” is not the right approach to treating patients with diabetes. “Other risk factors may offer bigger and more rapid benefits,” he said. “The benefits of glucose lowering are likely most relevant in type 1 diabetes and in early type 2 diabetes, and the benefits of glucose lowering on vascular disease appear to take a long time. Avoid severe hypoglycemia, especially in older patients with type 2 diabetes. This last point may be particularly relevant for those in poor control.”
Dr. Reaven reported having no relevant financial disclosures.