When Is Intensive Glucose Control Beneficial for Heart Health?
Click To Enlarge: Comparison of subgroup effects based on subgroup-specific rates of major adverse cardiovascular events (MACE). Subgroups were ordered from left to right by event rates in pooled data including both ACCORD and VADT studies. A. Event rates in each subgroup across both treatment arms (“All”, purple), among those randomized to standard glycemic control (“Standard”, blue), and among those randomized to intensive glycemic control (“Intensive”, green). Dotted lines show the event rates of MACE in the full sample (purple), in those randomized to standard glycemic control (blue), and in those randomized to intensive glycemic control (green). B. Risk differences of MACE associated with standard versus intensive glycemic control, stratified by study and subgroup with subgroups ordered from left to right by increasing MACE event rates in the full sample including pooled data from both studies. Positive risk differences reflect higher MACE and negative risk differences reflect lower MACE in intensive glycemic control compared to standard glycemic control. Blue and green dotted lines represent the average treatment effect of intensive versus standard glycemic control on MACE in the ACCORD and VADT studies, respectively. Source: Cardiovasc Diabetol. 2022; 21: 58.
AURORA, CO — One size doesn’t fit all, even when it comes to deciding which Type 2 diabetes patients would derive cardiovascular benefit from intensive glycemic control.
That is the conclusion of a new data-driven analysis that provided evidence supporting the diabetes treatment guideline recommendation of intensive glucose lowering in diabetes patients with low cardiovascular risk. The study led by researchers from the University of Colorado and the VA Eastern Colorado Healthcare System also emphasized that intensive glycemic control could be beneficial in some patients at higher cardiovascular risk.
Pointing out that evidence to guide individual Type 2 diabetes treatment is limited, the report published in Cardiovascular Diabetology analyzed heterogeneous treatment effects (HTE) of intensive glycemic control in Type 2 diabetes patients on major adverse cardiovascular events (MACE) in the Action to Control Cardiovascular Risk in Diabetes Study (ACCORD) and the Veterans Affairs Diabetes Trial (VADT). Representatives from the Hines, IL, VA Hospital and the Phoenix VAMC also participated in the research.
A focus on 12,042 patients in the two randomized trials was used to identify HTE of intensive vs. standard glycemic control on MACE in patients with Type 2 diabetes. The evaluation involved five variables—hemoglobin glycation index, estimated glomerular filtration rate, fasting glucose, age, and body mass index—to delineate eight subgroups. MACE risk difference in those groups ranged from -5.1% (95% CI – 8.7, – 1.5) to 3.1% (95% CI 0.2, 6.0) (negative values represent lower MACE associated with intensive glycemic control).
Researchers reported that intensive glycemic control was associated with lower MACE in pooled study data in subgroups with low (-4.2% [95% CI -8.1, -1.0]), intermediate (-5.1% [95% CI -8.7, -1.5]), and high (-4.3% [95% CI -7.7, -1.0]) MACE rates with consistent directions of effect in ACCORD and VADT alone.
The authors discussed how specialty society guidelines recognize Type 2 diabetes patient heterogeneity and recommend individualized treatment decisions about medication choices and glycemic control intensity, especially taking into account comorbidity burden and age.
“Real-world data, however, suggests widespread clinical inertia in diabetes care, potentially reflecting the paucity of evidence to guide treatment individualization,” according to the study. “Thus, tools to identify individuals for whom intensive glycemic control may be beneficial are needed, especially for reducing risk of cardiovascular disease, which remains the leading cause of mortality in type 2 diabetes patients.”
The authors suggested that subgroup analysis of randomized trials can offer evidence to guide individualized intensification of glycemic control for cardiovascular risk reduction. For their study, they used The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study and the Veterans Affairs Diabetes Trial (VADT), which did not find associations of intensive glycemic control with MACE.
“However, prior subgroup analysis of both the ACCORD and VADT trials suggest heterogeneous treatment effects (HTE),” they advised. “Individuals without a history of cardiovascular events prior to randomization or whose baseline hemoglobin A1c (HbA1c) was ≤ 8.0% in the ACCORD trial demonstrated a reduction in the primary outcome of MACE in the intensive treatment group. Similarly, intensive glycemic control was associated with reduced cardiovascular events in VADT trial participants with lower coronary artery calcium scores.”
Another option, according to the researchers, is machine learning, which “provides hypothesis-free approaches to evaluating patient subgroups based on combinations of variables. In this study, we aimed to address evidence gaps for Type 2 diabetes treatment individualization to mitigate cardiovascular disease risk using a hypothesis-free, data-driven method—causal forests machine learning to identify HTE of intensive glycemic control on MACE in the ACCORD and VADT studies.”
Worse Outcomes
The study determined that three subgroups, representing 34% of the combined ACCORD and VADT sample, “had consistent associations of intensive glycemic control with cardiovascular benefit in pooled data and in ACCORD and VADT separately, and two subgroups (34% of the combined ACCORD and VADT sample) demonstrated worse cardiovascular outcomes associated with intensive glycemic control in pooled data and in ACCORD and VADT separately.”
A consistent pattern of cardiovascular benefit or harm of intensive glycemic control in relation to cardiovascular risk was not identified in the subgroups, however, the authors pointed out.
For example, Subgroup 4 “demonstrated lower MACE associated with intensive glycemic control in the pooled sample, the ACCORD trial, and the VADT trial samples. Aside from a BMI ≥ 28 kg/m2, this was a relatively healthy subgroup of trial participants: age < 61 years, glucose ≤ 228 mg/dL, eGFR ≥ 69 mL/min/1.73m2, and low HGI bounded between -0.3 and 0.84. Consistent with these clinical characteristics, this subgroup had the lowest rate of MACE in the pooled sample of the ACCORD and VADT studies. Moreover, intensive glycemic control was not associated with all-cause mortality in this subgroup across both trials, providing reassurance that cardiovascular disease risk reduction was not offset by higher non-cardiovascular mortality.”
That information supported current treatment guidelines calling for intensive glycemic control targets in diabetes patients who are younger with few medical comorbidities.
The study’s analysis also identified lower MACE associated with intensive glycemic control in Subgroup 1, which had the highest risk of cardiovascular events, however.
Researchers described how their results could be used in real-world practice, stating, “Although we found one subgroup, Subgroup 4, in which intensive glycemic control was associated with fewer cardiovascular events, we would not interpret this result as advocating for treating similar real-world patients to an HbA1c target < 6%. That a similar benefit was observed in the VADT study and in the ACCORD study—which had very different HbA1c targets—suggests that a more intensive glycemic control strategy may be beneficial for certain patients without targeting specific HbA1c thresholds.”
A factor that should be considered, they wrote, is that increasing evidence that glucagon-like peptide-1 receptor agonists and sodium glucose co-transporter-2 inhibitors can improve cardiovascular outcomes in patients with diabetes independent of effects on glycemia.
“In sum, using data from two randomized trials of intensive glycemic control in type 2 diabetes patients, we found subgroups defined by combinations of HGI, eGFR, serum glucose, BMI, and age that exhibited different associations of intensive glycemic control with major adverse cardiovascular events,” researchers concluded. “This hypothesis-free, data driven approach identified a subset of patients consisting of younger trial participants with overweight/obesity, low HGI, preserved renal function, and lower serum glucose levels that may benefit from intensive glycemic control to lower MACE, consistent with contemporary guidelines for the care of diabetes patients.”
“We also highlight that potential benefit of intensive glycemic control to lower MACE was not clearly correlated with underlying risk of MACE in subgroups,” they added, “suggesting that clinical decision-making for diabetes treatment intensity based primarily on cardiovascular risk estimation may miss patient subgroups at high cardiovascular risk who might benefit from intensive glycemic control.”
- Edward JA, Josey K, Bahn G, Caplan L, Reusch JEB, Reaven P, Ghosh D, Raghavan S. Heterogeneous treatment effects of intensive glycemic control on major adverse cardiovascular events in the ACCORD and VADT trials: a machine-learning analysis. Cardiovasc Diabetol. 2022 Apr 27;21(1):58. doi: 10.1186/s12933-022-01496-7. PMID: 35477454; PMCID: PMC9047276.
