Intensive Glucose-Lowering Therapy Reduces Cardiovascular Disease Events in Veterans Affairs Diabetes Trial Participants With Lower Calcified Coronary Atherosclerosis

Abstract

OBJECTIVEThis study investigated the hypothesis that baseline calcified coronary atherosclerosis may determine cardiovascular disease events in response to intensive glycemic control within the Veterans Affairs Diabetes Trial (VADT).RESEARCH DESIGN AND METHODSAt baseline, 301 type 2 diabetic participants in the VADT, a randomized trial comparing the effects of intensive versus standard glucose lowering on cardiovascular events, had baseline coronary atherosclerosis assessed by coronary artery calcium (CAC) measured by computed tomography. Participants were followed over the 7.5-year study for development of cardiovascular end points.RESULTSDuring a median follow-up duration of 5.2 years, 89 cardiovascular events occurred. Although intensive glucose-lowering therapy did not significantly reduce cardiovascular events in the substudy cohort as a whole, there was evidence that the response was modified by baseline CAC, as indicated by significant P values for treatment by log(CAC + 1) interaction terms in unadjusted and multivariable-adjusted models (0.01 and 0.03, respectively). Multivariable-adjusted hazard ratios (HRs) for the effect of treatment indicated a progressive diminution of benefit with increasing CAC. Subgroup analyses were also conducted for clinically relevant CAC categories: those above and below an Agatston score of 100. Among those randomized to intensive treatment, for the subgroup with CAC >100, 11 of 62 individuals had events, while only 1 of 52 individuals with CAC ≤100 had an event. The multivariable HR for intensive treatment for those with CAC >100 was 0.74 (95% CI 0.46–1.20; P = 0.21), while for the subgroup with CAC ≤100, the corresponding HR was 0.08 (0.008–0.77; P = 0.03), with event rates of 39 and 4 per 1,000 person-years, respectively.CONCLUSIONSThese data indicate that intensive glucose lowering reduces cardiovascular events in those with less extensive calcified coronary atherosclerosis.

Strategies for Optimizing Glycemic Control and Cardiovascular Prognosis in Patients With Type 2 Diabetes Mellitus

“…13 Although certainly not definitive, these findings from VADT and AC-CORD suggest that intensive glucose control may reduce CV events in patients with a shorter duration of DM and in those who do not have significant preexisting CAD. 7,14 After a median follow-up of 5 years, the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial showed no difference between intensive control and standard control groups in macrovascular outcomes. [13][14][15] Mean HbA 1c values achieved in the ADVANCE study were 6.5% in the intensive control group and 7.3% in the standard control group.…”

“…7,14 After a median follow-up of 5 years, the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial showed no difference between intensive control and standard control groups in macrovascular outcomes. [13][14][15] Mean HbA 1c values achieved in the ADVANCE study were 6.5% in the intensive control group and 7.3% in the standard control group. 11 Similar to ACCORD and VADT, the rate of combined primary end point (composite of microvascular and macrovascular events) was significantly lower with intensive vs conservative glucose control among patients who did not have established CV disease at baseline.…”

Interpretation of cardiovascular outcome trials in type 2 diabetes needs a multiaxial approach

“…Overall the glycemic differences between the treatment arms were small and the primary outcome was neutral, however, patients with shorter diabetes duration (i.e., less than 5 years) had reduced risk [hazard ratio (HR) = 0.74 (95%CI: 0.54, 1.01)] for the composite primary CV endpoint as compared to those with longer disease duration [5-10 years HR = 0.81 (95%CI: 0.58, 1.13); > 10 years HR = 1.22 (95%CI: 0.98, 1.53); interaction with treatment P-value 0.014]. Another interesting observation in the context of degree of vasculopathy as a potential determinant for the effect of an intervention stems from the veterans affairs diabetes trial (VADT) [13] . The VADT tested whether intensive glucose control (targeted/achieved HbA1c < 6.0%/6.9%) vs conventional (targeted/achieved HbA1c < 9.0%/8.9%) could reduce CV risk in 1791 patients with long-standing T2D [13] .…”

“…Another interesting observation in the context of degree of vasculopathy as a potential determinant for the effect of an intervention stems from the veterans affairs diabetes trial (VADT) [13] . The VADT tested whether intensive glucose control (targeted/achieved HbA1c < 6.0%/6.9%) vs conventional (targeted/achieved HbA1c < 9.0%/8.9%) could reduce CV risk in 1791 patients with long-standing T2D [13] . Although intensive glucoselowering therapy did not significantly reduce CV events in the study cohort as a whole, there was evidence that the response was modified by baseline CAC.…”

Incorporating Incretin-Based Therapies Into Clinical Practice: Differences Between Glucagon-Like Peptide 1 Receptor Agonists and Dipeptidyl Peptidase 4 Inhibitors

“…[24][25][26][27] However, the effect of intensive therapy on macrovascular disease is still unclear; epidemiological evidence and data from recent trials suggest there are benefits, particularly if treatment is initiated early in the course of the disease and in patients with a shorter duration of DM (less burden of CHD). [28][29][30][31][32] Two recent meta-analyses of clinical studies that evaluated intensive vs standard therapy and the risk of cardiovascular outcomes concluded that intensive therapy significantly reduced the risk of cardiovascular events but not cardiovascular death or all-cause mortality. 33,34 Continued research on the pathophysiology and potential new treatments for patients with type 2 DM is warranted despite improved efforts to reach glycemic targets.…”