Diabetes Cardiovascular Risk Research Articles

Protective effect of intensive glucose lowering therapy on all-cause mortality, adjusted for treatment switching using G-estimation method, the ACCORD trial

Previous analysis of the action to control cardiovascular risk in diabetes showed an increased risk of mortality among patients receiving intensive glucose lowering therapy using conventional regression method with intention to treat approach. This method is biased when time-varying confounder is affected by the previous treatment. We used 15 follow-up visits of ACCORD trial to compare the effect of time-varying intensive vs. standard treatment of glucose lowering drugs on cardiovascular and mortality outcomes in diabetic patients. The treatment effect was estimated using G-estimation and compared with accelerated failure time model using two modeling strategies. The first model adjusted for baseline confounders and the second adjusted for both baseline and time-varying confounders. While the hazard ratio of all-cause mortality for intensive compared to standard therapy in AFT model adjusted for baseline confounders was 1.17 (95% CI 1.01–1.36), the result of time-dependent AFT model was compatible with both protective and risk effects. However, the hazard ratio estimated by G-estimation was 0.64 (95% CI 0.39–0.92). The results of this study revealed a protective effect of intensive therapy on all-cause mortality compared with standard therapy in ACCORD trial.

Carbamylated lipoproteins in diabetes.

Diabetic dyslipidemia is characterized by quantitative and qualitative abnor-malities in lipoproteins. In addition to glycation and oxidation, carbamylation is also a post-translational modification affecting lipoproteins in diabetes. Patients with type 2 diabetes (T2D) exhibit higher levels of carbamylated low-density lipoproteins (cLDL) and high-density lipoproteins (cHDL). Accumulating evidence suggests that cLDL plays a role in atherosclerosis in diabetes. cLDL levels have been shown to predict cardiovascular events and all-cause mortality. cLDL facilitates immune cell recruitment in the vascular wall, promotes accumulation of lipids in macrophages, and contributes to endothelial dysf-unction, endothelial nitric oxide-synthase (eNOS) inactivation and endothelial repair defects. Lastly, cLDL induces thrombus formation and platelet aggregation. On the other hand, recent data have demonstrated that cHDL serum level is independently associated with all-cause and cardiovascular-related mortality in T2D patients. This relationship may be causative since the atheroprotective properties of HDL are altered after carbamylation. Thus, cHDL loses the ability to remove cholesterol from macrophages, to inhibit monocyte adhesion and recruitment, to induce eNOS activation and to inhibit apoptosis. Taken together, it seems very likely that the abnormalities in the biological functions of LDL and HDL after carbamylation contribute to atherosclerosis and to the elevated cardiovascular risk in diabetes.

A prediction model on incident ESKD among individuals with T2D and CKD

BackgroundDiabetes is the leading cause of end-stage kidney disease (ESKD). This study aimed to predict incident ESKD among individuals with T2D and CKD. MethodThe Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial data were split into a training set and a validation set by a ratio of 7:3. A dynamic time-varying Cox model was fit to predict the development of incident ESKD. Significant predictors were identified from a list of candidate variables, including demographic characteristics, physical exam results, laboratory results, medical history, drug information, and healthcare utilization. Model performance was evaluated by Brier score and C statistics. Decomposition analysis was conducted to assess the variable importance. Patient-level data from Harmony Outcome clinical trial and CRIC study were used for external validation. ResultsA total of 6982 diabetes patients with CKD were used for model development, with a median follow-up of four years and 312 ESKD events. The significant predictors for the final model were female sex, race, smoking status, age at T2D diagnosis, SBP, HR, HbA1c, estimated glomerular filtration rate (eGFR), urine albumin-creatinine ratio (UACR), retinopathy event occurring in last year, antihypertensive drug use, and an interaction term between SBP and female. The model demonstrated good performance in discrimination (C-statistic 0.764 [95 % CI 0.763–0.811]) and calibration (Brier Score 0.0083 [95 % CI 0.0063–0.0108]). The top 3 most important predictors in the prediction model were eGFR, retinopathy event, and UACR. Acceptable discrimination (C-statistic: 0.701 [95 % CI 0.665–0.716]; 0.86 [95 % CI 0.847–0.872]) and calibration (Brier Score: 0.0794 [95 % CI 0.0733–0.1022]; 0.0476 [95 % CI 0.0440, 0.0506]) were demonstrated in the Harmony Outcome and CRIC data, respectively. ConclusionThe dynamic risk prediction of incident ESKD among individuals with T2D can be a useful tool to support better disease management to lower the risk of developing ESKD.

In Memoriam: Richard H. Grimm, Jr, MD, MPH, PhD (August 22, 1946-September 8, 2022).

In Memoriam: Richard H. Grimm, Jr, MD, MPH, PhD (August 22, 1946-September 8, 2022).

Abstract P347: Measures of Microvascular Complications Varies Across Racial/Ethnic Groups Over a Seven Year Period: Post-Hoc Analysis of Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial Data

Introduction: Type 2 diabetes (T2D) microvascular complications is a major public health issue that disproportionately affects people of color in the U.S. and Canada. There is limited understanding of racial/ethnic disparities in the longitudinal natural history of microvascular complications. We aimed to address this gap in knowledge by examining racial/ethnic differences in microvascular complication-related measures over seven years among T2D adults living in the U.S. and Canada. Hypothesis: We assessed the hypothesis that measures of microvascular complications vary by race/ethnic group over a period of seven years. Methods: From 10,251 Action to Control Cardiovascular Risk in Diabetes (ACCORD) (2003-2009) trial participants, we derived 6,683 participants having a baseline and ≥ two years of outcome recordings for our analysis (baseline mean age 62 ± 6.6 years, and 11 ± 7.4 years of diabetes diagnosis). In this longitudinal study, we used T2D microvascular measurements recorded at baseline, yearly for seven years, and during a trial exit period. Neuropathy-related measures analyzed was the Michigan Neuropathy Screening Instrument (MNSI); Nephropathy-related measures included the glomerular filtration rate (eGFR) by four-variable Modification of Diet in Renal Disease equation (ml/min/1.73 m 2 ), urine albumin (mg/dl), and urine albumin : creatinine (mg/g). We examined differences in measurement among Black (n 1 = 1,176), White (n 2 = 4,282), and Other race adults (n 3 = 1,229). We used multigroup latent growth modeling to compare models from fully constrained to unconstrained means, covariances, and residual variances models. Results: MNSI, eGFR, and urine albumin significantly differed across racial/ethnic groups (ΔX 2 MNSI (2) = 231.8, p<0.001; ΔX 2 eGFR (2) = 489.2, p<0.001; ΔX 2 urine-albumin (2) = 194.6, p<0.001). We noticed that at least one of the means and covariances differed across racial/ethnic groups. The average MNSI trajectory for Other race/ethnicity (intercept=1.88, slope=-0.08) were better than that for Black (intercept=2.07, slope=-0.09) and White adults (intercept=2.67, slope=-0.14). The average eGFR trajectories for Black (intercept=88.86, slope=-1.16) and Other race/ethnicity (intercept=85.68, slope=-1.15) were better than that for White adults (intercept=82.59, slope=-1.36). However, average urine albumin trajectories for Black adults were worst (intercept=10.77, slope=0.98) followed by Other race/ethnicity (intercept=9.36, slope=0.73) and White adults (intercept=7.65, slope=0.57). Conclusion: Trajectories of microvascular complication-related measures appear to vary by racial/ethnic group. Other race adults, with primarily consists of Hispanics, appeared to at lower risk of neuropathy for years than Black and White adults. Nephropathy outcomes could vary across racial/ethnic group depending on how nephropathy is defined.

Longer time in blood pressure target range improves cardiovascular outcomes among patients with Type 2 diabetes: A secondary analysis of a randomized clinical trial

AimsTo examine the prognostic value of time in target range (TIR) with adverse outcomes and validate it with common blood pressure (BP) metrics among patients with Type 2 diabetes mellitus. MethodsWe performed a post hoc analysis of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial. TIR for each subject was calculated using linear interpolation and an SBP target range of 110 to 130 mmHg. Cox models were used to assess the association of TIR and other BP metrics with the rate of clinical outcomes. ResultsA higher TIR (61.9–100.0 %) was associated with a 46 % reduction in major adverse cardiovascular events (MACE) (hazard ratio [HR]:0.54; 95 % CI: 0.43, 0.67) compared with TIR 0–22.9 %. Results were similar for stroke (0.19; 0.10, 0.36), myocardial infarction (0.67; 0.51, 0.89), heart failure (0.47; 0.33, 0.66), cardiovascular death (0.63; 0.42, 0.93) and all-cause mortality (0.70; 0.54, 0.91). Further analyses suggested a curvilinear association of TIR with MACE, and this association was independent with baseline, final SBP, mean SBP, or visit-to-visit SBP variability. ConclusionsLonger TIR is associated with lower cardiovascular risk and may add value as an outcome measure for hypertension control studies among patients with diabetes.

Association of vitamin and/or nutritional supplements with fall among patients with diabetes: A prospective study based on ACCORD and UK Biobank.

To assess the associations of vitamin and/or nutritional supplements (VNS) with falls among patients with diabetes. 9,141 and 21,489 middle-aged participants with diabetes from Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and UK Biobank were included. Use of VNS was collected at baseline, and fall events were recorded using annual questionnaires in ACCORD and electric records in UK Biobank during follow-up. The associations of VNS use with fall risk were analyzed using logistic regression models in ACCORD and Fine-Gray sub-distribution hazard models in UK Biobank. The role of specific supplements was also estimated in UK Biobank, adjusting for confounding factors and multiple comparisons. 45.9% (4,193/9,141, 5.5 median follow-up years) patients in ACCORD and 10.5% (2,251/21,489, 11.9 median follow-up years) in UK Biobank experienced fall and in-patient events during follow-up, respectively. In ACCORD, VNS using was associated with an increased risk of fall (full-adjusted odds ratio [OR]: 1.26, P < 0.05). In UK Biobank, despite no significant association between VNS overall and in-patient fall, vitamin B, calcium, and iron using increased the risk of falls significantly (full-adjusted hazard ratio range: 1.31-1.37, P < 0.05). Use of specific VNS increased the risk of fall among patients with diabetes. The non-indicative use of nutritional supplements for patients with diabetes might be inadvisable.

Pyridoxamine prevents increased atherosclerosis by intermittent methylglyoxal spikes in the aortic arches of ApoE-/- mice

Methylglyoxal (MGO) is a reactive glucose metabolite linked to diabetic cardiovascular disease (CVD). MGO levels surge during intermittent hyperglycemia. We hypothesize that these MGO spikes contribute to atherosclerosis, and that pyridoxamine as a MGO quencher prevents this injury. To study this, we intravenously injected normoglycemic 8-week old male C57Bl6 ApoE-/- mice with normal saline (NS, n = 10) or 25 µg MGO for 10 consecutive weeks (MGOiv, n = 11) with or without 1 g/L pyridoxamine (MGOiv+PD, n = 11) in the drinking water. We measured circulating immune cells by flow cytometry. We quantified aortic arch lesion area in aortic roots after Sudan-black staining. We quantified the expression of inflammatory genes in the aorta by qPCR. Intermittent MGO spikes weekly increased atherosclerotic burden in the arch 1.8-fold (NS: 0.9 ± 0.1 vs 1.6 ± 0.2 %), and this was prevented by pyridoxamine (0.8 ± 0.1 %). MGOiv spikes increased circulating neutrophils and monocytes (2-fold relative to NS) and the expression of ICAM (3-fold), RAGE (5-fold), S100A9 (2-fold) and MCP1 (2-fold). All these changes were attenuated by pyridoxamine. This study suggests that MGO spikes damages the vasculature independently of plasma glucose levels. Pyridoxamine and potentially other approaches to reduce MGO may prevent excess cardiovascular risk in diabetes

Predicted lean body mass, fat mass, and heart failure in patients with type 2 diabetes mellitus

High body mass index (BMI) is associated with a higher risk of heart failure (HF) in patients with new-onset type 2 diabetes mellitus (T2DM). However, limited studies have investigated the independent association between fat mass or lean body mass and HF risk among T2DM patients with cardiovascular disease (CVD) or high CVD risk. To investigate the association between fat mass index (FMI, kg/m2) or lean BMI (LBMI, kg/m2) and HF risk. This was a post hoc analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. Cox proportional-hazards models were applied to evaluate the association of FMI, LBMI, and BMI with HF risk. Discordant analysis was performed to compare the magnitude of this associations. HF occurred in 356 participants (3.7%). After adjusting for confounding factors, higher FMI values were independently associated with HF risk (HR: 1.72, 95% CI: 1.15-2.57, each 1 SD increase in FMI); LBMI was a protective risk factor for HF (HR: 0.58, 95% CI: 0.38-0.87,). After further adjusting for FMI, the association between BMI and HF risk (HR, 0.97; 95% CI, 0.67-1.42) disappeared. Compared with concordant values below the medians, discordant FMI above the median with BMI below yielded an HR of 1.78 (95% CI: 1.14-2.78) for HF. In contrast, BMI above the median with FMI below was not associated with HF risk (HR: 1.09, 95% CI: 0.57-2.09). The risk of HF conferred by higher BMI was primarily driven by the association between FMI and HF. After adjusting for BMI, LBMI played a protective role.

Glucose and HbA1c variability and time in range (TIR)

Glycated hemoglobin (HbA1c) is the pillar of diabetes management, but does not capture blood glucose fluctuations over time. Recent data suggest that additional glucose-related metrics might improve prevention of the increased cardiovascular risk in diabetes. Variabilities in both blood glucose and HbA1cappear to represent additional, independent risk factors for diabetes complications. Continuous glucose monitoring also allows calculation of a new, intuitive metric, i.e., time in range (TIR), which is strictly related to glucose variability and is also an independent risk factor for diabetes complications. Here, we review the main findings on the influence of TIR, glucose, and HbA1cvariability on the development of complications and highlight the possible role of novel drugs in improving glucose variability.

Glukose- und HbA1c-Variabilität sowie Zeit im Zielbereich (TIR)

Glycated hemoglobin (HbA1c) is the pillar of diabetes management, but does not capture blood glucose fluctuations over time. Recent data suggest that additional glucose-related metrics might improve prevention of the increased cardiovascular risk in diabetes. Variabilities in both blood glucose and HbA1c appear to represent additional, independent risk factors for diabetes complications. Continuous glucose monitoring also allows calculation of a new, intuitive metric, i.e., time in range (TIR), which is strictly related to glucose variability and is also an independent risk factor for diabetes complications. Here, we review the main findings on the influence of TIR, glucose, and HbA1c variability on the development of complications and highlight the possible role of novel drugs in improving glucose variability.

The role of blood pressure control in the prevention of cardiorenal disease in patients with chronic kidney disease.

Optimal blood pressure (BP) control has been debated between two schools of thought: standard BP control to a goal of systolic BP (SBP) <140 mmHg and intensive BP control with a goal of <120 mmHg. Currently only three randomized controlled trials (RCTs) have been performed to address this question, which will be included in this review: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group (2010), the Systolic Blood Pressure Intervention Trial (SPRINT; 2015) and the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial, performed in Chinese participants in 2021 [1–3]. Further insights into BP management to prevent cardiovascular disease (CVD) events in patients with chronic kidney disease (CKD) will also be reviewed here. Unfortunately, there is less data from RCTs for determining optimal BP levels to prevent renal disease progression. Only three studies in non-diabetic CKD—SPRINT, the Modification of Diet in Renal Disease (MDRD) study and the African American Study of Kidney Disease and Hypertension (AASK)—and no studies in patients with CKD due to type 2 diabetes mellitus (T2DM) have been performed to investigate this problem and, to date, the ideal management protocol for clinicians is lacking. In this review we will also include investigations from historically important studies focusing on control of BP and its effects in patients with CKD, including the MDRD study (1993), the AASK study (2001) and the Ramipril Efficacy In Nephropathy 2 (REIN-2) study (2005) [4–6]. The study of CKD patients in the SPRINT study [7] also provides an important perspective on the importance of more intensive BP control on cardiovascular events. It is also important to note that despite the same body of evidence from these clinical studies, guideline committees have come up with different recommendations for target BP, further complicating the question of optimal BP targets. This opinion paper is targeted towards NDT readers with an interest in kidney disease in relation to BP goals and cardiovascular outcomes.

Cardiac autonomic dysfunction and risk of incident stroke among adults with type 2 diabetes.

There is a dearth of data on the association between cardiac autonomic neuropathy (CAN) with incident stroke among individuals with diabetes mellitus. We evaluated this association in a large sample of adults with type 2 diabetes. Participants with type 2 diabetes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study without atherosclerotic cardiovascular disease at baseline were included. CAN was assessed at baseline by heart rate variability (HRV) indices and QT index (QTI) calculated from 10-s resting electrocardiograms. HRV was assessed using standard deviation of all normal-to-normal R-Rs intervals (SDNN) and root mean square of successive differences between normal-to-normal R-R intervals (rMSSD). CAN was defined based on several composite measures of SDNN, QTI, resting heart rate and peripheral neuropathy. We used Cox proportional hazards regression to generate hazard ratios (HR) and 95% confidence intervals (CI) for incident stroke in relation to CAN. A total of 3493 participants (mean age 62.2 years, 44.5% women, 62.9% White) were included. Over a median follow-up of 5.0 years, 50 stroke cases occurred (incidence rate 3.0/1000 person-years [95% CI 2.2-3.9]). After adjusting for confounders, low HRV was associated with a higher risk of stroke (HR of 2.20 [95% CI 1.23-3.93] and 1.88 [95% CI 1.04-3.41] for low SDNN and rMSSD, respectively). Participants with CAN (defined as lowest quartile of SDNN and highest quartiles of QTI and heart rate) had a 5.7-fold greater risk of stroke (HR 5.70, 95% CI 2.49-13.08). CAN was independently associated with an increased risk of incident stroke in a large cohort of adults with type 2 diabetes.

Influence of Baseline Diastolic Blood Pressure on the Effects of Systolic Blood Pressure Lowering on Cognitive Function in Type 2 Diabetes Mellitus.

Lowering of systolic blood pressure (SBP) in patients with low diastolic blood pressure (DBP), can further lower DBP. This can potentially decrease cerebral perfusion and cognition. We examined the influence of baseline DBP on the effect of lowering SBP on cognition. This is a post hoc analysis of the Memory in Diabetes (MIND) substudy (N = 1,430) of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (NCT00000620). Standard neuropsychological tests (Digit Symbol Substitution Test [DSST], Mini-Mental State Examination [MMSE], Rey Auditory Verbal Learning Test [RAVLT], and Stroop test) were performed at baseline and months 20 and 40. We compared the effects of intensive (goal SBP <120 mm Hg) vs. standard (goal SBP <140 mm Hg) SBP control on the changes in the 4 test scores from baseline to the averages of months 20 and 40 across the range of baseline DBP using cubic spline terms. Mean age was 63 ± 6 years, 55% were women and 66% White. Participates with lower baseline DBP were older, had more cardiovascular events and a longer duration of diabetes. There was no difference in the change in DSST (-0.22; 95% CI -0.97, 0.52), MMSE (-0.14; 95% CI -0.34, 0.06), RAVLT (-0.12; 95% CI -0.29, 0.06), and Stroop interference (-0.47; 95% CI -1.76, 0.82) in the intensive vs. standard SBP intervention. There was no interaction between baseline DBP and change in scores with the SBP intervention. Intensive SBP reduction does not adversely affect cognition, even in those with low baseline DBP.

Considerations for Optimal Blood Pressure Target of Hypertension

Hypertension is a major risk factor for cardiovascular morbidity and mortality that has led to a huge public health burden. The optimal target of blood pressure (BP) to prevent cardiovascular complications remains unclear. Based on the results of the Systolic BP Intervention Trial (SPRINT) in 2015, the 2017 American College of Cardiology/American Heart Association guidelines for diagnosis and management of high BP in adults has changed the diagnostic threshold from 140/90 to 130/80 mmHg, and the target BP to 130/80 mmHg for nearly all hypertensive patients diagnosed using the new criteria. However, the findings from the SPRINT trial were to an extent contrasting with the results of previous large randomized controlled trials, namely Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Secondary Prevention of Small Subcortical Strokes (SPS3). Besides, the 2018 European Society of Cardiology/European Society of Hypertension guidelines and the 2018 Chinese guidelines have maintained the conventional threshold and recommended target of 140/90 mmHg for most hypertensive patients. Given the special measurement of BP in the SPRINT trial and using an automated measurement system, the intensive systolic BP target of 120 mmHg provided by the SPRINT trial was not widely adopted. Most recently, the Strategy of BP Intervention in the Elderly Hypertensive Patients (STEP) trial, with a higher systolic BP target of 110 to 130 mmHg in the intensive group, confirmed the benefit and safety of intensive BP control in patients with hypertension, in accordance with the SPRINT trial. Here, the results from randomized controlled trials, meta-analyses, and other observational research studies, have been reviewed to evaluate the optimal target of BP treatment and the threshold of diagnostic criteria for hypertension.

Development and validation of a model to predict cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease

BackgroundAmong individuals with atherosclerotic cardiovascular disease (ASCVD), type 2 diabetes mellitus (T2DM) is common and confers increased risk for morbidity and mortality. Differentiating risk is key to optimize efficiency of treatment selection. Our objective was to develop and validate a model to predict risk of major adverse cardiovascular events (MACE) comprising the first event of cardiovascular death, myocardial infarction (MI), or stroke for individuals with both T2DM and ASCVD.MethodsUsing data from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), we used Cox proportional hazards models to predict MACE among participants with T2DM and ASCVD. All baseline covariates collected in the trial were considered for inclusion, although some were excluded immediately because of large missingness or collinearity. A full model was developed using stepwise selection in each of 25 imputed datasets, and comprised candidate variables selected in 20 of the 25 datasets. A parsimonious model with a maximum of 10 degrees of freedom was created using Cox models with least absolute shrinkage and selection operator (LASSO), where the adjusted R-square was used as criterion for selection. The model was then externally validated among a cohort of participants with similar criteria in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial. Discrimination of both models was assessed using Harrell’s C-index and model calibration by the Greenwood-Nam-D’Agostino statistic based on 4-year event rates.ResultsOverall, 1491 (10.2%) of 14,671 participants in TECOS and 130 (9.3%) in the ACCORD validation cohort (n = 1404) had MACE over 3 years’ median follow-up. The final model included 9 characteristics (prior stroke, age, chronic kidney disease, prior MI, sex, heart failure, insulin use, atrial fibrillation, and microvascular complications). The model had moderate discrimination in both the internal and external validation samples (C-index = 0.65 and 0.61, respectively). The model was well calibrated across the risk spectrum—from a cumulative MACE rate of 6% at 4 years in the lowest risk quintile to 26% in the highest risk quintile.ConclusionAmong patients with T2DM and prevalent ASCVD, this 9-factor risk model can quantify the risk of future ASCVD complications and inform decision making for treatments and intensity.

Association of the cumulative triglyceride-glucose index with major adverse cardiovascular events in patients with type 2 diabetes

BackgroundThe triglyceride-glucose (TyG) index is a reliable surrogate marker of insulin resistance and is associated with major adverse cardiovascular events (MACEs) in patients with type 2 diabetes mellitus (T2DM). However, the long-term effect of the TyG index on the incidence of MACEs remains unclear. We aimed to investigate the association between the cumulative TyG index and the risk of MACEs in patients with T2DM.MethodsThis post-hoc analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial assessed patients’ (T2DM > 3 months) cumulative TyG index and MACE data from the study database. Five fasting blood glucose and triglyceride measurements, at baseline and the first four visits, were taken from 5695 participants who had not experienced MACEs. Cumulative exposure to the TyG index was calculated as the weighted sum of the mean TyG index value for each time interval (value × time). Multivariable-adjusted Cox proportional hazard models and restricted cubic spline analysis were used to determine the association between the cumulative TyG index and MACEs. The incremental predictive value of the cumulative TyG index was further assessed.ResultsOver a median follow-up of 5.09 years, 673 (11.82%) MACEs occurred, including 256 (4.50%) cardiovascular disease (CVD) deaths, 288 (5.06%) non-fatal myocardial infarctions (MIs), and 197 (3.46%) strokes. The risk of developing MACEs increased with the cumulative TyG index quartile. After adjusting for multiple potential confounders, the hazard ratios for the very high cumulative TyG index group versus the low group were 1.59 (95% confidence interval [CI], 1.17–2.16), 1.97 (95% CI 1.19–3.26), and 1.66 (95% CI 1.02–2.70) for overall MACEs, CVD death, and non-fatal MI, respectively. Restricted cubic spline analysis also showed a cumulative increase in the risk of MACEs with an increase in the magnitude of the cumulative TyG index. The addition of the cumulative TyG index to a conventional risk model for MACEs improved the C-statistics, net reclassification improvement value, and integrated discrimination improvement value.ConclusionsIn patients with T2DM, the cumulative TyG index independently predicts the incidence of MACEs, and monitoring the long-term TyG index may assist with optimized-for-risk stratification and outcome prediction for MACEs.Trial registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000620.

Remnant Cholesterol and Its Visit-to-Visit Variability Predict Cardiovascular Outcomes in Patients With Type 2 Diabetes: Findings From the ACCORD Cohort

OBJECTIVERemnant cholesterol (remnant-C) predicts atherosclerotic cardiovascular disease, regardless of LDL-cholesterol (LDL-C) levels. This study assessed the associations between remnant-C and cardiovascular outcomes in type 2 diabetes.RESEARCH DESIGN AND METHODSThis post hoc analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial used patient (type 2 diabetes >3 months) remnant-C and major adverse cardiovascular event (MACE) data from the study database. The associations between remnant-C and MACEs were evaluated using Cox proportional hazards regression analyses. We examined the relative MACE risk in remnant-C versus LDL-C discordant/concordant groups using clinically relevant LDL-C targets by discordance analyses.RESULTSThe baseline analysis included 10,196 participants, with further visit-to-visit variability analysis including 9,650 participants. During follow-up (median, 8.8 years), 1,815 patients (17.8%) developed MACEs. After adjusting for traditional cardiovascular risk factors, each 1-SD increase in remnant-C was associated with a 7% higher MACE risk (hazard ratio [HR] 1.07, 95% CI 1.02–1.12, P = 0.004). In the fully adjusted model, the visit-to-visit remnant-C variability calculated using logSD (HR 1.41, 95% CI 1.18–1.69, P < 0.001) and logARV (HR 1.45, 95% CI 1.22–1.73, P < 0.001) was associated with MACEs. Residual lipid risk (remnant-C ≥31 mg/dL) recognized individuals at a higher MACE risk, regardless of LDL-C concentrations. Within each LDL-C subgroup (>100 or ≤100 mg/dL), high baseline remnant-C was associated with a higher MACE risk (HR 1.37, 95% CI 1.09–1.73, P = 0.007; HR 1.22, 95% CI 1.04–1.41, P = 0.015, respectively).CONCLUSIONSRemnant-C levels were associated with MACEs in patients with type 2 diabetes independent of LDL-C, and visit-to-visit remnant-C variability helped identify those with higher cardiovascular risk.

143-OR: Mapping Genetic Determinants of Blood Glucose Control in the Action to Control Cardiovascular Risk in Diabetes Study Group (ACCORD)

The hemoglobin glycation index (HGI) is the difference between observed HbA1c and predicted HbA1c from FPG using linear regression. HGI is an important biomarker of clinical management/drug treatment outcomes and can identify individuals at high risk for multiple adverse events and outcomes before the appearance of clinical symptoms. Here, we sought to test if variation in HGI has genetic determinants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial using a genome-wide association approach (N = 7913) . We subsequently replicated the top hits (P &amp;lt; 1e-5) in the Atherosclerosis Risk in Communities Study (ARIC; N = 3741) . An intergenic SNP rs73407935 (7q11.22) was associated with HGI (P = 5.8e-10) with the locus replicating in ARIC. Further, multiple variants at suggestive genome-wide significance in discovery (P &amp;lt; 5e-6) replicated in ARIC including variants near or in ASAH1 (P = 2.4e-6) , a region previously associated with risk of CAD in T2D, LRRC4C (P = 2.4e-6) , SHLD1 (P = 3.7e-6) and FAM22B (P = 2.5e-6) . The top 2 replicated SNPs in FAM22B are characterized eQTLs for expression of multiple genes in cells from pancreas, brain, and the immune system, including TRAF4, PROCA1, and RPL23A. Many SNPs associated with HGI were distinct from those associated with FPG or HbA1c. In ACCORD, sex-specific HGI associations with SNPs in or near GALNT11 in females (P = 5e-9) and HECW2 (P = 1.5e-8) in males were observed. Further, analysis of 544 Hispanics revealed associations of a strong eQTL variant near USF1 (rs2516837; P = 1.5e-09) and SNPs near NXNL2/SPIN1 (rs141006133; P = 6.9e-9) with HGI. This work represents the first evaluation of the genetic etiology of HGI. We identified and replicated variants that merit further study in the development of precision medicine for treatment of T2D. The results of the stratified analyses highlight the potential importance of heterogeneity in these efforts. Disclosure J.S.House: None. D.M.Rotroff: Research Support; Novo Nordisk, Stock/Shareholder; Clarified Precision Medicine. V.Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. J.M.Hempe: None. J.Mychaleckyj: None. A.Doria: Research Support; Novo Nordisk Foundation. J.B.Buse: Consultant; Alkahest, Anji, AstraZeneca, Boehringer Ingelheim International GmbH, Cirius Therapeutics, Inc., Eli Lilly and Company, Fortress biotech, GentiBio, Glycadia, Glyscend, Janssen Pharmaceuticals, Inc., Mellitus Health, Moderna, Inc., Pendulum Therapeutics, Praetego, LLC, Stability Health, Valo, Zealand Pharma A/S, Other Relationship; Adocia, AstraZeneca, Eli Lilly and Company, Intarcia Therapeutics, Inc., MannKind Corporation, Novo Nordisk, Sanofi, Senseonics, vTv Therapeutics, Research Support; AstraZeneca, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, vTv Therapeutics, Stock/Shareholder; Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Praetego, LLC, Stability Health. A.Motsinger-reif: None. Funding NHLBI RO1HL110380NIDDK P30DK124723NCATS UL1TR002489

Living Alone Is Not Associated With Cardiovascular Events and Hypoglycemia in Patients With Type 2 Diabetes Mellitus

Objective:Living alone is often associated with reduced social support. However, there are limited data on the relationship between living alone and cardiovascular events or hypoglycemia in patients with type 2 diabetes mellitus (T2DM). This study reports a post-hoc analysis of the “Action to Control Cardiovascular Risk in Diabetes (ACCORD)” study.Research Design and MethodsThe Cox proportional hazard models were used to compare the hazard ratios (HRs) for the adverse health events selected as primary endpoints in the study participants; these were compared between those living alone and those living with others. The primary outcomes were hypoglycemia requiring any assistance (HAA), hypoglycemia requiring medical assistance (HMA), and major cardiovascular events (MACEs, including cardiac death, non-fatal myocardial infarction (MI), and non-fatal stroke). Our study included 10,249 participants (2,078 living alone) with a follow-up period of 4.91 ± 1.22 years.ResultsAfter a multivariable adjustment, the risk of HAA, HMA, and MACEs did not differ significantly between participants living alone and those living with others (HAA, HR: 0.88, 95% CI: 0.75–1.04, P = 0.13; HMA, HR: 1.11, 95% CI: 0.92–1.34, P = 0.26; MACEs, HR: 0.98, 95% CI: 0.80–1.19, P = 0.82). Participants living alone had higher levels of glycated hemoglobin in the middle follow-up period than those living with others.ConclusionsIn patients with T2DM, living alone did not increase the risk of cardiovascular events (cardiac death, non-fatal MI, or non-fatal stroke) and hypoglycemia. Patients living alone had higher Hb1AC levels than those living with others. Clinicians should consider an effective blood glucose control regardless of their living arrangement.