Association Between Long-Term Visit-to-Visit Hemoglobin A1c and Cardiovascular Risk in Type 2 Diabetes: The ACCORD Trial

Background: To explore the association between visit-to-visit variability of glycated hemoglobin (HbA1c) and cardiovascular outcomes in the patients with type 2 diabetes mellitus (T2DM) of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study.Methods: We conducted a post-hoc analysis on the ACCORD population including 9,544 participants with T2DM. Visit-to-visit variability of HbA1c was defined as the individual SD, coefficient of variation (CV), and variability independent of the mean (VIM) across HbA1c measurements. The clinical measurements included primary outcome [the first occurrence of non-fatal myocardial infarction (MI), non-fatal stroke or cardiovascular death], total mortality, cardiovascular death, non-fatal MI event, non-fatal stroke, total stroke, heart failure, macrovascular events, and major coronary events (CHD).Results: Over a median follow-up of 4.85 years, 594 and 268 participants experienced all-cause mortality and cardiovascular mortality, respectively. After adjusting for baseline HbA1c levels and confounding factors, the adjusted hazard ratio (HR) comparing patients in the highest vs. the lowest quartile CV of HbA1c variability was 1.61 (95% CI 1.29–2.00) for the primary outcome. Similar trends for secondary outcome were also observed. There was no association between HbA1c fluctuation and non-fatal stroke. Noticeably, there was 66% greater risk for the all-cause mortality among patients in the highest vs. the lowest quartile (HR 1.66, 95% CI 1.27–2.17).Conclusions: Greater variability of HbA1c is associated with higher risk for cardiovascular complications and all-cause death in T2DM. Our study stresses the significance of well-controlled glycemic levels for improving cardiovascular outcomes. Further randomized clinical trials are required to confirm these findings.

Severe Hypoglycemia and Incident Heart Failure among Adults With Type 2 Diabetes

Context The effect of severe hypoglycemia on the incidence of heart failure (HF) is unclear. Objective We evaluated the association of severe hypoglycemia with incident HF among individuals with type 2 diabetes. Methods We included participants with type 2 diabetes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. Severe hypoglycemia episodes were assessed during the initial 24 months following randomization and defined using two methods: symptomatic, severe hypoglycemic event requiring medical assistance (first definition) or requiring any assistance (second definition). Participants without HF at baseline and during the first 24 months of the study were prospectively followed for incident HF hospitalization. Multivariable Cox regression was used to generate adjusted hazard ratios (HR) for the association of severe hypoglycemia and incident HF. Results Among 9,208 participants (mean age 63 years, 38% female, 62% White), 365 had ≥ 1 episode of severe hypoglycemic. Over a median follow-up of 3 years, there were 249 incident HF events. After multivariable adjustment for relevant confounders, participants with severe hypoglycemia requiring medical assistance had a 68% higher relative risk of incident HF (HR 1.68, 95% CI 1.06-2.66), as compared to individuals who never experienced any episode of hypoglycemia. Severe hypoglycemia requiring any assistance was also associated with a 49% higher relative risk of HF (HR 1.49, 95% CI 1.01-2.21). Conclusion In a large cohort of adults with type 2 diabetes, severe hypoglycemia was independently associated with greater risk of incident HF.

Association of Predicted Lean Body Mass and Fat Mass With Incident Diabetic Nephropathy in Participants With Type 2 Diabetes Mellitus: A Post Hoc Analysis of ACCORD Trial

BackgroundLean body mass (LBM) and fat mass (FM) have been shown to have different associations with several chronic diseases but little is known about the sex-specific association of LBM and FM with diabetic nephropathy (DN) risk among participants with diabetes.MethodsParticipants from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study was used in a post hoc analysis to examine the association of predicted LBM index (LBMI) and FM index (FMI) with incident DN risk (defined as a composite outcome of three types of predefined DN). Because of sex differences in body composition, analyses were conducted separately using sex-specific quartiles of predicted LBMI and FMI.ResultsOf the 9,022 participants with type 2 diabetes (5,575 men and 3,447 women) included in this study, 5,374 individuals developed DN (3,396 in men and 1,978 in women). Higher quartiles of LBMI were associated with a reduced risk of DN while higher quartiles of FMI were associated with an increased higher risk of DN among men but not women. Compared with the lowest quartile, the fully adjusted hazard ratios (HRs) and 95% confidence intervals (CIs)for the highest quartile of predicted LBMI and FMI were respectively 0.83 (95% CI 1.71 – 0.96) and 1.23 (95% CI 1.06-1.43) among men; and 0.92 (95% CI 0.63 – 1.33) and 1.14 (95% CI 0.79 – 1.63) among women.ConclusionsAmong participants with diabetes, predicted LBMI was inversely associated with risk of DN while predicted FMI was positively associated with an increased risk of incident DN among men but not women. Trial registration: ClinicalTrials.gov., no. NCT00000620.

The Impact of Triglyceride-Glucose Index On Incident Cardiovascular Events in Patients With Type 2 Diabetes Mellitus

Background: Previous studies reported the prognostic value of the triglyceride-glucose (TyG) index in the course of cardiovascular (CV) diseases. Still, it remains unclear whether baseline and trajectories of TyG index are prospectively associated with incident CV events among patients with type 2 diabetes mellitus (T2DM).Methods: We performed a secondary analysis in patients with long-lasting T2DM from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. The primary outcome was the first occurrence of adverse CV events including nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes, and the TyG index was measured at 11 visits. Cox proportional hazards regression analysis was used to observe the association between baseline and trajectories of TyG index and adverse CV outcomes.Results: During a median follow-up period of 8.8 years, 1,815 (17.8%) developed at least one primary endpoint event. After adjusting for traditional cardiovascular risk factors, each 1-SD increase in the TyG index was associated with a 19.00% higher risk of adverse CV events, similar in individuals categorized by TyG index quartiles. Four distinct trajectories of TyG indexes were identified- low (16.17%), moderate (40.01%), high (34.60%), and very high (9.30%). Among these, moderate, high, and very high TyG index trajectories had a greater risk of future incident adverse CV events than low TyG index trajectories after multivariate adjustments for traditional risk factors. Particularly, a similar association was noticed in the TyG index and the occurrence of coronary heart disease.Conclusions: The findings of this study suggest that both baseline and trajectories of TyG index have a significant association with the occurrence of adverse CV events in patients with T2DM. (Trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000620)

Individualizing the target diastolic blood pressure in patients being treated for hypertension and diabetes

Background/Introduction The J-curve hypothesis in hypertension is related to an increased risk of cardiovascular events associated with both too high and too low diastolic blood pressure (DBP) values. European Society of Cardiology recommended DBP in the range of 70–80 mm Hg as a treatment target for subjects with hypertension, regardless of age, history of cardiovascular disease (CVD) or diabetes mellitus (DM) presence. Such a recommendation is based on studies performed in subjects with prior CVD. There is no scientific evidence to support a target DBP of 70–80 mmHg in people with DM and without history of CVD. Purpose The aim of the study is to determine the relationship between DBP and cardiovascular risk according to age and the presence of CVD in people with DM. Methods The ACCORD study dataset (participants with diabetes) available from National Heart, Lung and Blood Institute was used to perform the analysis. The DBP value during the study was defined as the mean of all DBP measurements obtained during the study individually for each participant. The composite endpoint (CE) was defined as myocardial infarction, stroke, exacerbation of heart failure or cardiovascular death. The relationship between the DBP value during the study and the risk of CE was presented using the Cox proportional hazard model and spline curves. This analysis was performed for 4 sub-populations defined on the basis of 2 criteria: age <65 years and the presence of CVD in the past. Each model was adjusted for other cardiovascular risk factors (age, sex, smoking, systolic blood pressure, chronic kidney disease). Results The data of 4,733 participants of the ACCORD BP study were analyzed. The table (Figure 1) presents the baseline characteristics of the 4 sub-populations and CE occurrence. For each sub-population studied, a Cox model describing the relationship between DBP during the study and CE risk was developed and presented in the Figure 2. In subjects with CVD the J-curve relationship between DBP and CE risk was observed. Among subjects without prior CVD, no J-curve relationship was observed. Conclusions Optimal DBP treatment target in subjects with CVD and DM is slightly lower than the currently recommended range of 70–80 mm Hg. DBP values in the range of 70–80 mm Hg should not be recommended as the treatment target for subjects with DM and no history of CVD. FUNDunding Acknowledgement Type of funding sources: None. Figure 1 Figure 2

Anthropometric Measures and Incident Diabetic Nephropathy in Participants With Type 2 Diabetes Mellitus

BackgroundThe prevalence of diabetes is on the rise globally coupled with its associated complications, such as diabetic nephropathy (DN). Obesity has been identified as a risk factor for the development of DN but it is still unclear which obesity index is the best predictor of incident DN.MethodsData from the participants with type 2 diabetes mellitus (T2DM) in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study were used to examine the sex-specific association between waist circumference (WC), waist-to-height ratio (WHtR), and body mass index (BMI) with incident DN risk.ResultsAmong the 8,887 participants with T2DM (5,489 men and 3,398 women), 5,296 participants (3,345 men and 1,951 women) developed the DN composite outcome during a follow-up period of 24302 person-years. Among men, null associations were observed between all anthropometric measures with incident DN in the multivariate analysis although the 3rd quartile of WHtR showed marginally significant results (P = 0.052). However, among women, both central and general obesity measures were associated with increased risks of incident DN. Compared with participants in the WC <88 cm category, the fully adjusted HR and 95% CI for those in the ≥88 cm of WC was 1.35 (95% CI 1.15-1.57). Compared with the lowest quartile, the fully adjusted HRs and 95% CIs for the 2nd to the 4th quartile of WHtR were 1.09 (95% CI 0.96-1.25), 1.12 (95% CI 0.98-1.28), and 1.14 (95% CI 1.00-1.30) respectively; also, compared with the normal BMI category, the fully adjusted HRs and 95% CIs for class I – class III obese were 1.36 (95% CI 1.10 – 1.67), 1.43 (95% CI 1.16 – 1.78) and 1.32 (95% CI 1.05 – 1.66) respectively.ConclusionsAmong participants with T2DM, higher levels of both central and general obesity indexes were associated with DN risk among women but not in men. Women with T2DM should maintain a healthy weight targeted at reducing both central and general obesity to enhance nephroprotection. Trial registration: ClinicalTrials.gov., no. NCT00000620.

Up and down waves of glycemic control and lower-extremity amputation in diabetes

Lower extremity amputations (LEA) are associated with a high mortality and medical expenditure. Diabetes accounts for 45% to 70% of LEA and is one of the most potent risk factors for peripheral artery diseases (PAD). The existence of a link between the recent relaxation of glycemic targets and the resurgence of LEA is suggested from the analysis of adult participants in the National Health and Nutrition Examination Survey (NHANES) between 2010 and 2015, when diabetes-related LEA increased by more than 25% associated with a decline in glycemic control. Indeed, in “the perfect wave” of NHANES, including the years 2007–2010, there was the highest number of diabetic people with hemoglobin A1c (HbA1c), non-high-density lipoprotein (HDL) cholesterol and blood pressure levels at their respective targets, associated with the lowest number of LEA. Until now, the ACCORD study, testing the role of aggressive vs conventional glucose control, and the LEADER trial, evaluating the effects of liraglutide versus placebo, have shown a reduced incidence of LEA in people with type 2 diabetes. The results of ongoing clinical trials involving glucagon-like peptide-1 receptor agonists (GLP-1RA, liraglutide or semaglutide) hopefully will tell us whether the wider use of these drugs may provide additional vascular benefits for diabetic people affected by PAD to decrease their risk of LEA.

Visual acuity outcomes after cataract surgery in type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study

AimsTo evaluate visual acuity (VA) outcomes of cataract surgery, and factors associated with good visual outcomes, among a population with diabetes.MethodsParticipants with type 2 diabetes enrolled in The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study and ACCORD-eye substudy. 1136 eyes of 784 ACCORD participants receiving cataract surgery during follow-up (2001–2014) were included. Of these, 362 eyes had fundus photographs gradable for diabetic retinopathy. The main outcome measure was the achievement of postoperative VA of 20/40 or better.ResultsIn the sample of 1136 eyes, 762 eyes (67.1%) achieved good visual outcome of 20/40 or better. Factors predictive of good visual outcome were higher level of educational attainment (college vs some high school, OR 2.35 (95% CI 1.44 to 3.82)), bilateral cataract surgery (OR 1.55 (1.14 to 2.10)) and preoperative VA (20/20 or better vs worse than 20/200, OR 10.59 (4.07 to 27.54)). Factors not significantly associated (p>0.05) included age, sex, race, smoking, diabetes duration, blood pressure, lipid levels and haemoglobin A1C (HbA1C). In the subsample of 362 eyes, absence of diabetic retinopathy was associated with good visual outcome (OR 1.73 (1.02 to 2.94)).ConclusionAmong individuals with diabetes, two-thirds of eyes achieved good visual outcome after cataract surgery. Notable factors associated with visual outcome included preoperative VA and diabetic retinopathy, but not HbA1C, underscoring that while certain ocular measures may help evaluate visual potential, systemic parameters may not be as valuable. Sociodemographic factors might also be important considerations. Although the current visual prognosis after cataract surgery is usually favourable, certain factors still limit the visual potential in those with diabetes.

HbA1c trajectory and cardiovascular outcomes: an analysis of data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study

Background: We investigated the associations between glycated hemoglobin (HbA1c) trajectories and cardiovascular outcomes using data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. Methods: We used HbA1c values within the first 2 years of treatment for modeling with a latent class growth model. Groups of HbA1c trajectories were modeled separately in the standard (group 1–group 4) and intensive (group 5–group 8) treatment arms. The primary outcome in the ACCORD study was a composite of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes. Effects of HbA1c trajectories on cardiovascular outcomes were analyzed using a Cox-proportional hazard model. Results: Baseline HbA1c levels for the eight trajectories (group 1–group 8) were 7.8 ± 0.8, 8.2 ± 0.9, 9.3 ± 1.1, 9.6 ± 1.2, 7.8 ± 0.7, 10.1 ± 0.8, 8.3 ± 0.7, and 9.5 ± 1.1%, respectively. The respective values after 2 years of treatment were 7.0 ± 0.6, 7.7 ± 0.7, 8.5 ± 0.9, 10.3 ± 1.3, 6.2 ± 0.4, 6.5 ± 0.6, 7.2 ± 0.6, and 8.5 ± 1.1%. After a median follow-up of 4.8 years, group 5 and group 6 had similar outcomes compared with group 1 (reference group). In contrast, group 3, group 4, and group 8 had higher risks of the primary composite outcome compared with group 1. Conclusion: HbA1c trajectory was associated with cardiovascular outcomes in type 2 diabetes patients with high cardiovascular risk.

Increasing the uptake of long-acting reversible contraception in general practice: the Australian Contraceptive ChOice pRoject (ACCORd) cluster randomised controlled trial longitudinal follow-up protocol

IntroductionThrough addressing main barriers to the uptake of long-acting reversible contraceptives (LARCs) among Australian women, the Australian Contraceptive ChOice pRoject (ACCORd) trialled an educational intervention targeting general practitioners (GPs) and provided those in the intervention group with a rapid referral service for quick insertion. The cluster randomised controlled trial resulted in greater uptake of LARC in the intervention group. This protocol paper describes a longitudinal follow-up to the ACCORd Study to assess the long-term efficacy and cost-effectiveness of the intervention.Methods and analysisWomen participants (patients of ACCORd GPs) completed a baseline, 6-month and 12-month survey. These participants will be invited to complete an additional follow-up survey 3 years post completion of their baseline interview. Based on the original ACCORd Study tools, the online survey will address long-term outcomes including contraceptive continuation rates and reproductive history, any unintended pregnancies, satisfaction and concerns with their current contraceptive method, and an assessment of quality of life. We will analyse data using binary regression models with generalised estimating equations and robust standard errors to account for clustering.DiscussionDemonstration of sustained use, effectiveness at reducing unwanted pregnancies and cost-effectiveness of this strategy among this cohort of Australian primary care patients, will strengthen the policy and programme urgency of addressing wider dissemination of these strategies and replicating the study elsewhere.Ethics and disseminationThe ACCORd Study received approval from the Monash University Human Research Ethics Committee: CF16/188-201000080. Additionally, an amendment to conduct this 3-year longitudinal follow-up survey has been approved. The trial follow-up outcomes will be disseminated through formal academic pathways, including journal articles, national and international conferences and reports as well as using more ‘mainstream’ strategies such as seminars, workshops and media engagement. Additionally, outcomes will be communicated through policy briefs to Australian state and federal governments.Trail registration numberThis trial is registered with the Australian and New Zealand Trials Registry ACTRN12615001346561. Recruitment and data collection have been completed for the baseline, 6-month and 12-month surveys. Data collection for the 3-year survey commenced in August 2019.