BARI 2D Trial Research Articles

Quality of Life in Older Adults With Stable Ischemic Heart Disease and Diabetes Mellitus: A Post Hoc Analysis of the BARI 2D Trial

Studies on the long-term differences in quality-of-life (QoL) metrics after treatment for stable ischemic heart disease (SIHD) in older adults with diabetes mellitus are lacking. Older patients (age ≥65 years) in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial were stratified into those who received intensive medical therapy (IMT) only versus revascularization (percutaneous coronary intervention [PCI] vs coronary artery bypass graft surgery [CABG]) with Optimal Medical Therapy (OMT). Self-health score, Duke activity status index (DASI), energy rating, and health distress rating at 5 years were compared using multivariable linear regression. A total of 929 older adults were included, of whom 469 (50.5%) underwent medical therapy alone, 302 (32.5%) underwent PCI, and 158 (17.0%) had CABG. Patients who underwent CABG were more likely to have proximal left anterior descending coronary artery disease, chronic total occlusion, and higher myocardial jeopardy index. At 5 years of follow-up, no differences in self-health score, DASI, energy rating, and health distress rating were observed between PCI and IMT. There are also no differences in the 4 QoL measures between CABG and IMT alone. However, the DASI was marginally higher with CABG but not statistically significant (mean difference 3.88, 95% confidence interval -0.10 to -7.86, p = 0.057). At 5 years of follow-up, no differences in QoL measures were observed between PCI and CABG with OMT versus OMT alone in older adult patients with diabetes mellitus and SIHD. Future blinded randomized trials are necessary to investigate the impact of SIHD treatment in the older adult population, considering the risks associated with multimorbidity, polypharmacy, frailty, and cognitive impairment.

Do Clinical Outcomes and Quality of Life Differ by the Number of Antianginals for Stable Ischemic Heart Disease? Insights from the BARI 2D Trial

Medical therapy, including antianginal treatment, is the cornerstone in the management of stable ischemic heart disease (SIHD). However, it remains unclear whether combining antianginal agents provides benefits beyond monotherapy in terms of quality of life (QoL) and cardiovascular outcomes. We used data from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial, which compared cardiovascular and QoL outcomes in patients with SIHD and diabetes mellitus randomized to revascularization with intensive medical therapy or intensive medical therapy alone. We categorized patients into 3 groups: ≥2 versus 1 versus 0 antianginals. We compared patient characteristics, QoL metrics, and cardiovascular end points at baseline and at 5 years, creating a multivariable model to adjust for key clinical confounders. Of 2,368 patients, 348 patients (14.7%) were on 0 antianginals, 1,020 patients (43.1%) were on 1 antianginal, and 1,000 patients (42.2%) were on ≥2 antianginals at baseline. The most common antianginal class was β blockers. At baseline, patients on 0 antianginals had better QoL metrics (self-health score, Duke activity status index, and energy rating) than patients on ≥2 antianginals. However, at the 1-year follow-up, patients taking only 1 antianginal showed greater QoL improvement than those taking 0 antianginal, without any incremental benefit in QoL metrics seen in patients taking ≥2 antianginal agents, even after adjusting for multiple covariates such as age, heart failure, diabetes control, and myocardial jeopardy index. Lastly, at the 5-year follow-up, after adjustment, there were no differences in all-cause mortality, major adverse cardiovascular events, or myocardial infarction between patients taking different numbers of antianginals. Adults on a single antianginal for SIHD and diabetes mellitus had similar or better improvements in QoL than those on 2 or more antianginal agents at 1 year of follow-up. These findings merit further research to better understand the impact of medical therapy intensity on QoL in patients with SIHD and associated co-morbidities.

Abstract 16279: Does the Number of Antianginals Influence Clinical Outcomes and Quality of Life in Stable Ischemic Heart Disease? Insights From the BARI2D Trial

Introduction: Medical therapy is essential for managing stable ischemic heart disease (SIHD), including anti-anginals. remains unclear whether combining anti-anginal agents provides benefits beyond monotherapy in terms of QoL and cardiovascular outcomes. Hypothesis: The use of a single anti-anginal (β-Blockers, calcium channel blockers, or nitrates) is non-inferior to ≥2 anti-anginals Methods: We utilized data from the BARI-2D trial, which compared cardiovascular and QoL outcomes in patients with SIHD and diabetes mellitus (DM) randomized to revascularization with intensive medical therapy or intensive medical therapy alone. We categorized patients into three groups: ≥2 vs 1 vs 0 anti-anginals. We compared patient characteristics, QoL metrics, and cardiovascular endpoints at baseline and at 5 years, creating a multivariable model to adjust for key clinical confounders. Results: Among 2,368 patients, 348 patients (14.7%) were on 0 anti-anginals, 1,020 patients (43.1%) were on 1 anti-anginal, and 1,000 patients (42.2%) were on ≥2 anti-anginals at baseline. The most common anti-anginal class was β-Blockers. At baseline, patients on 0 anti-anginals had better QoL metrics than patients on ≥2 anti-anginals. However, at a 1-year follow-up, patients taking only 1 anti-anginal showed greater QoL improvement than those taking 0 anti-anginal; this superiority in QoL metrics was not seen in patients taking ≥2 anti-anginal agent, even after adjusting for multiple covariates such as age, heart failure, diabetes control and myocardial jeopardy index. (Figure 1) Lastly, at 5-year follow-up, after adjustment, there were no differences in all-cause mortality, major adverse cardiovascular events, or myocardial infarction between patients taking different numbers of anti-anginals. Conclusion: Treating adults with SIHD and DM with a single anti-anginal was at least as effective in improving QoL compared to two or more anti-anginal agents at one year of follow-up.

D-24 | Quality of Life After Revascularization versus Medical Therapy in Older Adults With Stable Ischemic Heart Disease at 5 Year Follow-up in the BARI2D Trial

D-24 | Quality of Life After Revascularization versus Medical Therapy in Older Adults With Stable Ischemic Heart Disease at 5 Year Follow-up in the BARI2D Trial

Development and validation of optimal phenomapping methods to estimate long-term atherosclerotic cardiovascular disease risk in patients with type 2 diabetes.

Type 2 diabetes is a heterogeneous disease process with variable trajectories of CVD risk. We aimed to evaluate four phenomapping strategies and their ability to stratify CVD risk in individuals with type 2 diabetes and to identify subgroups who may benefit from specific therapies. Participants with type 2 diabetes and free of baseline CVD in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial were included in this study (N = 6466). Clustering using Gaussian mixture models, latent class analysis, finite mixture models (FMMs) and principal component analysis was compared. Clustering variables included demographics, medical and social history, laboratory values and diabetes complications. The interaction between the phenogroup and intensive glycaemic, combination lipid and intensive BP therapy for the risk of the primary outcome (composite of fatal myocardial infarction, non-fatal myocardial infarction or unstable angina) was evaluated using adjusted Cox models. The phenomapping strategies were independently assessed in an external validation cohort (Look Action for Health in Diabetes [Look AHEAD] trial: n = 4211; and Bypass Angioplasty Revascularisation Investigation 2 Diabetes [BARI 2D] trial: n = 1495). Over 9.1years of follow-up, 789 (12.2%) participants had a primary outcome event. FMM phenomapping with three phenogroups was the best-performing clustering strategy in both the derivation and validation cohorts as determined by Bayesian information criterion, Dunn index and improvement in model discrimination. Phenogroup 1 (n = 663, 10.3%) had the highest burden of comorbidities and diabetes complications, phenogroup 2 (n = 2388, 36.9%) had an intermediate comorbidity burden and lowest diabetes complications, and phenogroup 3 (n = 3415, 52.8%) had the fewest comorbidities and intermediate burden of diabetes complications. Significant interactions were observed between phenogroups and treatment interventions including intensive glycaemic control (p-interaction = 0.042) and combination lipid therapy (p-interaction < 0.001) in the ACCORD, intensive lifestyle intervention (p-interaction = 0.002) in the Look AHEAD and early coronary revascularisation (p-interaction = 0.003) in the BARI 2D trial cohorts for the risk of the primary composite outcome. Favourable reduction in the risk of the primary composite outcome with these interventions was noted in low-risk participants of phenogroup 3 but not in other phenogroups. Compared with phenogroup 3, phenogroup 1 participants were more likely to have severe/symptomatic hypoglycaemic events and medication non-adherence on follow-up in the ACCORD and Look AHEAD trial cohorts. Clustering using FMMs was the optimal phenomapping strategy to identify replicable subgroups of patients with type 2 diabetes with distinct clinical characteristics, CVD risk and response to therapies.

Abstract 15971: Gender, Race, and Age Specific Baseline Predictors of All-Cause Mortality in BARI2D Trial Identified by Machine Learning

Introduction: NHLBI supported Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes trial (BARI2D) (NCT00006305) evaluated patients with type 2 diabetes and coronary artery disease. Primary trial analysis found no significant differences in rates of all-cause mortality (ACM) among patients who underwent 1) prompt revascularization with medical therapy versus aggressive medical therapy alone and 2) insulin-sensitization medical strategies versus insulin-provision. We reused publicly available individual patient-level data from NHLBI Data Repository (BioLINCC) to perform hypothesis-generating secondary analysis by machine learning (ML), using random survival forest (RSF) to identify gender, race, and age specific baseline predictors for ACM. Methods: The total 2368 trial participants was separated into several subgroups based on gender (female and male), age (40-49, 50-59, 60-69, 70-80), and race (Non-Hispanic White, Hispanic White, Non-Hispanic Non-White, and Hispanic Non-White). RSF was performed on 84 baseline variables to identify predictors of the primary outcome, ACM. The top 10 predictors for each subgroup were tested in a Cox proportional hazards model Results: Top 10 predictors of ACM are shown in Table 1. Although anticipated cardiovascular (CV) and diabetic predictors appeared among the top predictors, at the same time, renal function biomarkers like serum creatinine, urine albumin/creatinine ratio, and serum potassium uniquely showed among the top 5 predictors across the gender, age, and race specific subgroups. Conclusions: Using ML, we uncovered in an unbiased fashion, gender, race and age groups specific unanticipated top baseline predictors of ACM in BARI2D trial. This highlights the value of gender, race and age groups specific predictors of outcomes for determining the efficacy of therapeutic interventions and help advance precision medicine.

1472-P: Association between Triglycerides and Residual Cardiovascular (CVD) Risk in Patients with Type 2 Diabetes and Established CVD: An Analysis of the BARI2D Trial

Background: While hypertriglyceridemia is a known risk factor for developing CVD, whether it poses residual risk in patients with type 2 diabetes mellitus (T2DM) and established CVD is under-studied. Methods: Using data from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial, we examined 2,307 patients with T2DM and CVD to determine the association of baseline fasting triglyceride (TG) levels with MACE (time to CV death, myocardial infarction (MI), or stroke) or CV death over a mean follow-up of 5.0 years. Results: At baseline, the mean fasting TG was 181 mg/dl with a median (Q1, Q3) of 148 (104, 219) mg/dl. Overall, 49.3% had TG≥ 150 mg/dl (N=1,167). Compared with those with TG&amp;lt;150 mg/dl, they were younger, more frequently Caucasian and with higher BMI. In unadjusted models, TGs were significantly associated with MACE and CV death (Table). This association did not remain after adjustment for multiple factors, including nonHDLc. Conclusions: In this analysis of patients with T2DM and known CVD, TGs were relatively high and were associated with CV outcomes, but not when other risk factors were taken into account. Thus, while TGs are clearly a marker of those with residual high risk for CV events in T2DM, whether they specifically need to be lowered awaits well conducted clinical trials. Disclosure N. Pagidipati: Research Support; Self; Amarin Corporation, Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Regenerative Medical Solutions, Sanofi. A. Navar: Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc. Research Support; Self; Janssen Pharmaceuticals, Inc. Other Relationship; Self; Amarin Corporation, Amgen Inc., Regeneron Pharmaceuticals, Sanofi. H. Mulder: None. D.M. Wojdyla: None. S. Philip: Employee; Self; Amarin Corporation. Stock/Shareholder; Self; Amarin Corporation. C.B. Granowitz: Employee; Self; Amarin Pharma Inc. Stock/Shareholder; Self; Amarin Pharma Inc. Funding Amarin Corporation

Strategies for glycemic control in nonobese and obese type 2 diabetic patients with coronary artery disease

BackgroundThis study aimed to assess strategies of insulin-providing (IP) or insulin-sensitizing (IS) therapy for glycemic control in nonobese diabetic patients with coronary artery disease (CAD) with possibly higher cardiovascular risk and lower insulin secretion than obese diabetic patients with CAD. MethodsWe used data from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial to calculate hazard ratio (HR) with 95% confidence interval (95%CI) for outcome events in patients with type 2 diabetes and CAD using Cox proportional hazard models. The comparison between the IP and IS groups was performed using the randomized design of the BARI 2D trial separately for nonobese (n = 1021) and obese (n = 1319) patients. The primary outcome was a composite endpoint including all-cause death, myocardial infarction, and stroke. ResultsDuring the follow-up, 231 nonobese and 295 obese patients had one confirmed primary outcome event. In nonobese patients, the risk of primary outcome events was significantly higher in the IP group than the IS group (HR: 1.30, 95%CI: 1.00–1.68, P = 0.04), whereas that in obese patients did not differ significantly between the two groups. Moreover, in nonobese patients, the risk of primary outcome events in those without abdominal obesity was significantly higher in the IP group than that in the IS group (HR: 1.51, 95%CI: 1.05–2.19, P = 0.02). There were no significant interactions between the strategy for glycemic control and various subgroups of nonobese patients. ConclusionsIn nonobese patients with type 2 diabetes and CAD, the IS treatment strategy may be more beneficial than the IP treatment strategy.

Thrombotic/Thrombolytic Balance as a Cardiac Treatment Determinant in Patients With Diabetes Mellitus and Coronary Artery Disease.

BackgroundThis study aimed to assess whether the plasminogen activator inhibitor‐1/tissue plasminogen activator (PAI‐1/tPA) ratio as a prothrombotic state is useful for optimizing cardiac treatment strategy.Methods and ResultsUsing BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial data, we used a Cox proportional hazard model to calculate hazard ratios with 95% CIs for cardiac events in patients receiving early revascularization (percutaneous coronary intervention or coronary artery bypass grafting) or medical therapy, separately in patients with low (n=1276) and high (n=894) PAI‐1/tPA ratios. The primary outcome was major cardiac events, which was a composite end point including cardiac death and nonfatal myocardial infarction. The mean±SD follow‐up period was 4.1±1.7 years. The risk of major cardiac events in patients with high PAI‐1/tPA ratio was significantly higher when receiving percutaneous coronary intervention (hazard ratio, 1.84; 95% CI, 1.16–2.93; P=0.01) than when receiving medical therapy, whereas that in patients with low PAI‐1/tPA ratio did not differ significantly between the groups (hazard ratio, 0.95; 95% CI, 0.66–1.36; P=0.77); the interaction between the cardiac treatment strategy and PAI‐1/tPA ratio was significant (P=0.02). However, regardless of the PAI‐1/tPA ratio, major cardiac event risk seemed to be lower in patients receiving coronary artery bypass grafting than in those receiving medical therapy.ConclusionsIn patients with type 2 diabetes mellitus and coronary artery disease, this study demonstrated that those with high PAI‐1/tPA ratio were at higher risks of major cardiac events when treated with percutaneous coronary intervention than when treated with intensive medical therapy.

Hypoglycemia and Elevated Troponin in Patients With Diabetes and Coronary Artery Disease

BackgroundDiabetic medications can cause hypoglycemia, which may lead to myocardial damage. ObjectivesThis study sought to determine whether hypoglycemia is associated with higher levels of high-sensitivity cardiac troponin T (hsTnT). MethodsThe BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial randomized patients with type 2 diabetes mellitus and stable coronary artery disease, and closely followed them for hypoglycemia over the first year. Hypoglycemia was classified by maximum severity and frequency. hsTnT was measured at baseline and 1 year, and analyzed using multivariable regression. ResultsOf 1,984 patients, follow-up hypoglycemia was absent in 1,026 (52%) patients, mild in 875 (44%), and severe in 83 (4%), and occurred less than weekly in 561 (28%) and greater than or equal to weekly in 397 (20%). hsTnT levels were associated with hypoglycemia: a median of 11.4 ng/l (interquartile range [IQR]: 8.1 to 17.3 ng/l) for none, 12.5 ng/l (IQR: 8.3 to 19.3 ng/l) for mild, and 13.7 ng/l (IQR: 9.9 to 24.9 ng/l) for severe hypoglycemia (p = 0.0001); and 12.5 ng/l (IQR: 8.3 to 18.1 ng/l) for less than weekly and 13.0 ng/l (IQR: 8.8 to 21.1 ng/l) for greater than or equal to weekly hypoglycemia (p = 0.0013). Severe hypoglycemia was associated with 34% higher 1-year hsTnT levels (p < 0.0001) in unadjusted analysis, 17% higher (p = 0.006) after adjustment for baseline factors unrelated to diabetes, and 6% higher (p = 0.23) after further adjustment for the duration and severity of diabetes. Hypoglycemia greater than or equal to weekly was associated with 14% higher hsTnT (p = 0.0003) in unadjusted analysis, 12% higher (p = 0.0002) after adjustment for baseline factors unrelated to diabetes, and 4% higher (p = 0.16) after adjustment for diabetes related factors. ConclusionsHypoglycemia was associated with elevated hsTnT levels, but this may be due to more severe diabetes in patients who developed hypoglycemia, rather than the direct result of hypoglycemia. (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes [BARI2D]; NCT00006305)

ASSOCIATION BETWEEN GLYCEMIC CONTROL AND MAJOR ADVERSE CARDIAC EVENTS IN PATIENTS WITH TYPE 2 DIABETES FOLLOWING CORONARY ARTERY BYPASS SURGERY: A SECONDARY ANALYSIS OF THE BARI 2D TRIAL

Patients with diabetes account for one-third of patients undergoing coronary artery bypass grafting (CABG), and have a higher long-term risk of major adverse cardiovascular events (MACE) after CABG compared to non-diabetics. The reason for this increased risk remains unclear; however, hyperglycemia may be a contributor. Guideline recommendations for long-term glycemic control after CABG range from target HbA1c concentrations of <7.0% to 7.1-8.5%. These recommendations were based on data from non-CABG patients, and no study has evaluated the long-term impact of glycemic targets on MACE post-CABG. We performed a secondary analysis of the BARI2D trial to evaluate the association between HbA1c and long-term MACE in patients with diabetes undergoing CABG. The BARI2D trial dataset was acquired from the NHLBI Data Repository. This trial enrolled patients with type 2 diabetes and coronary artery disease. Analyses were restricted to participants who underwent CABG at any point during study follow-up and had at least one HbA1c measurement after CABG. Date of the first post-CABG HbA1c measurement was considered the index date. The primary outcome was MACE (composite of death, MI, unstable angina, or repeat revascularization). Secondary outcomes included MACE components and heart failure. We used Cox proportional hazards models treating HbA1c as a time-dependent exposure (reference group: HbA1c 6.1-7.0%), to derive adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) adjusting for age, sex and baseline characteristics selected by stepwise regression. Sensitivity analyses were conducted using alternate exposure definitions (lowest HbA1c, HbA1c at baseline, HbA1c as a continuous outcome). P-values <0.05 were considered statistically significant. We included 549 patients followed over a median 46 months (interquartile range [IQR] 35-59). First post-CABG A1c occurred a median 7.5 months (IQR 7-14) after randomization into BARI2D. Compared to HbA1c 6.1-7.0%, HbA1c >8.0% was associated with an increased risk of MACE (HR 1.77, 1.01-3.10), whereas differences with HbA1c <6.0% (HRs 1.03, 0.54, 1.98) and 7.1-8.0% (HR 1.04, 0.60-1.81) were not significant. This association was strongest for unstable angina (HbA1c >8.0% vs 6.1-7.0% HR 5.21, 1.03-26.39). HbA1c <6.0% was associated with an increased risk of death (HR 2.41, 1.01-5.74). Other outcomes were not statistically significant. Results of sensitivity analyses were consistent with the primary analysis. Compared to a HbA1c 6.1-7.0%, HbA1c >8.0% was associated with a higher risk of MACE and unstable angina and HbA1c <6.0% was associated with a higher risk of death in patients with type 2 diabetes who underwent CABG.

Dual antiplatelet therapy versus aspirin monotherapy in diabetics with stable ischemic heart disease undergoing coronary artery bypass grafting.

Dual antiplatelet therapy (DAPT) in patients presenting with acute coronary syndrome (ACS) undergoing CABG is recommended to prevent recurrent ischemic events. The benefit of DAPT post-CABG in patients with stable ischemic heart disease (SIHD) is unknown. The aim of this study was to evaluate the utilization rate of DAPT and associated outcomes in patients with SIHD undergoing CABG via a secondary analysis of Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial data. In a post-hoc, nonrandomized analysis from the BARI 2D trial, we compared patients receiving DAPT and aspirin monotherapy within 90 days post-randomization. The primary outcome was the risk adjusted 5-year composite of all-cause mortality, nonfatal myocardial infarction (MI), or stroke. We analyzed patients assigned to prompt CABG treatment arm including both the insulin therapy assignments. Of 378 patients, within 90 days post-randomization, 59 (16%) patients received DAPT and 319 (84%) patients received aspirin alone. Cox proportional hazard analysis demonstrated that there was no significant difference in the 5-year composite event of death, MI, and stroke between DAPT and monotherapy cohorts [13 (22.0%) vs. 61 (19.1%); adjusted hazard ratio (HR): 1.06; 95% confidence interval (CI): 0.56 to 2.00; P=0.86]. There also was no significant difference at 1 year in the composite event [6 (10.2%) vs. 30 (9.4%); HR: 1.13; 95% CI: 0.46 to 2.79; P=0.79]. The use of DAPT in patients with diabetes post-CABG in this cohort was low. Compared with aspirin monotherapy, no associated differences were observed in cardiovascular outcomes. Larger prospective studies are needed to further elucidate this observation.

THE INFLUENCE MULTIMORBIDITY IN OLDER ADULTS WITH DIABETES AND STABLE ISCHEMIC HEART DISEASE

Long-term influence of multimorbidity in adults with stable heart disease is unknown. Using data from BARI 2D trial, we analyzed the effects of multimorbidity in young adults (YA) versus older adults (OA) with stable ischemic heart disease (IHD). Patients were randomized to: 1. IP versus IS therapy

Increased Hazard of Myocardial Infarction With Insulin-Provision Therapy in Actively Smoking Patients With Diabetes Mellitus and Stable Ischemic Heart Disease: The BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) Trial.

BackgroundIn the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial, randomization of diabetic patients with stable ischemic heart disease to insulin provision (IP) therapy, as opposed to insulin sensitization (IS) therapy, resulted in biochemical evidence of impaired fibrinolysis but no increase in adverse clinical outcomes. We hypothesized that the prothrombotic effect of IP therapy in combination with the hypercoagulable state induced by active smoking would result in an increased risk of myocardial infarction (MI).Methods and ResultsWe analyzed BARI 2D patients who were active smokers randomized to IP or IS therapy. The primary end point was fatal or nonfatal MI. PAI‐1 (plasminogen activator inhibitor 1) activity was analyzed at 1, 3, and 5 years. Of 295 active smokers, MI occurred in 15.4% randomized to IP and in 6.8% randomized to IS over the 5.3 years (P=0.023). IP therapy was associated with a 3.2‐fold increase in the hazard of MI compared with IS therapy (hazard ratio: 3.23; 95% confidence interval, 1.43–7.28; P=0.005). Baseline PAI‐1 activity (19.0 versus 17.5 Au/mL, P=0.70) was similar in actively smoking patients randomized to IP or IS therapy. However, IP therapy resulted in significantly increased PAI‐1 activity at 1 year (23.0 versus 16.0 Au/mL, P=0.001), 3 years (24.0 versus 18.0 Au/mL, P=0.049), and 5 years (29.0 versus 15.0 Au/mL, P=0.004) compared with IS therapy.ConclusionsAmong diabetic patients with stable ischemic heart disease who were actively smoking, IP therapy was independently associated with a significantly increased hazard of MI. This finding may be explained by higher PAI‐1 activity in active smokers treated with IP therapy.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00006305.

Insulin provision therapy and mortality in older adults with diabetes mellitus and stable ischemic heart disease: Insights from BARI-2D trial

ImportanceOptimal strategies for glucose control in very old adults with diabetes and stable ischemic heart disease (SIHD) are unclear. ObjectiveTo compare the effects of insulin provision (IP) therapy versus insulin sensitizing (IS) therapy for glycemic control in older (≥75years) and younger (<75years) adults with type II diabetes (DM) and SIHD. Design, setting, and participantsAdults enrolled in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) were studied. The BARI 2D study population (all with type II DM and SIHD) was randomized twice: (1) between revascularization plus intensive medical therapy versus intensive medical therapy alone, and (2) between IP versus IS therapies. The primary endpoint was all-cause-mortality over five-year follow-up. In this substudy outcomes related to IP vs. IS are assessed in relation to age. Adults aged ≥75years who received IP versus IS are compared to those <75years who received IP versus IS. Multivariate Cox regression analysis was used to evaluate the effects of IP vs. IS on outcomes in the two age groups. Results2368 subjects with SIHD and DM were enrolled in BARI 2D; 182 (8%) were ≥75years. Compared to younger subjects, the older cohort had lower BMI, higher diuretic use, worse kidney function, and increased history of heart failure. Within the older cohort, the IP and IS subgroups were similar in respect to baseline cardiovascular risk factors, medications, and coronary artery disease severity. During follow-up, the older subjects receiving IP therapy had higher cardiovascular mortality compared to those receiving IS therapy (16% vs. 11%, p=0.040). Using Cox proportional hazards analysis, the older IP subjects were at increased risk for all-cause-mortality (hazard ratio 1.89, CI 1.1–3.2, p=0.020). No mortality difference between IP and IS was observed in those <75years of age. Conclusion and relevanceAmong adults with diabetes and SIHD aged ≥75years, IP therapy may be associated with increased mortality compared to IS therapy. Additional studies are needed to further refine optimal treatment strategies for diabetes and SIHD in old age.

Abstract 12577: Markers of Residual Risk in Type 2 Diabetes and Stable Ischemic Heart Disease: Insights From the BARI 2D Trial

Background: In spite of aggressive preventive therapy, patients with type 2 diabetes (T2D) and stable ischemic heart disease (SIHD) remain at high risk for major cardiovascular events and death. Understanding the pathophysiologic determinants of that residual risk could help identify effective preventive therapies. Methods and Results: In this Ancillary Study of the BARI 2D trial, we examined the predictive value of biomarkers from 6 distinct pathophysiologic pathways in 2285 men and women with T2D and SIHD who were followed for a median (IQR) of 5.0 (4.1-6.0) years. The endpoint for this Ancillary Study was a composite of myocardial infarction, stroke, heart failure, or all-cause mortality. The 5-year Kaplan-Meier event rate was 31%. The pathophysiologic processes evaluated included dysglycemia (HbA1c), dyslipidemia (LDL-C), myocardial strain (NT-proBNP), myocardial injury (high-sensitivity cardiac troponin T [hsTnT]), subclinical inflammation (high-sensitivity C-reactive protein [hsCRP]), and nephropathy (presence/absence of macroalbuminuria). In Cox proportional hazards models adjusted for baseline risk factors, angiographic severity of disease, and ejection fraction, each marker except LDL-C was a significant predictor of outcome (Figure) in this population with 74% baseline statin use. After mutual adjustment for all 6 markers and baseline risk factors, the hazard ratio (95% CI) per 1-SD of natural logarithm transformed concentration was largest for NT-proBNP [1.29 (1.17, 1.42)], followed by hsTnT [1.16 (1.07, 1.26)], HbA1c [1.12 (1.03, 1.21)], and hsCRP [1.11 (1.03, 1.20). Macroalbuminuria was not a significant predictor after adjustment for the other markers (Figure). Conclusions: In this high-risk population of patients with type 2 diabetes and stable ischemic heart disease, strategies to target myocardial strain, myocardial injury, and subclinical inflammation may lead to improvements in cardiovascular outcome.

Abstract 11930: Sex Differences in Cardiac Troponin and the Risk of Death or Major Cardiovascular events in Men and Women With Diabetes and Coronary Artery Disease

Background: Circulating cardiac troponin T concentrations are higher in men than in women, but the biological causes and clinical implications of this observation are poorly understood. Methods and Results: We measured cardiac troponin T with a high-sensitivity assay (hsTnT) in 684 women and 1601 men with type 2 diabetes (T2D) and stable ischemic heart disease (SIHD) who were enrolled in the BARI 2D trial. Median (IQR) hsTnT was higher in men [12.4 ng/L (8.7-20.8)] than in women [9.1 ng/L (6.4-15.6); P&lt;0.0001] and a higher proportion of men (43.6%) than women (29.1%) were above the current established upper reference limit of 14 ng/L (P&lt;0.0001). Sex remained a significant predictor of natural log normalized hsTnT after adjusting for a wide array of covariables, including age, race, insulin use, renal function, ejection fraction, and HbA1c. Within quintiles of hsTnT measured at baseline, the 5-year incidence of the composite cardiovascular outcome of myocardial infarction, stroke, heart failure, or death was consistently higher in women than in men (Figure 1). In sex-stratified Cox models adjusting for possible confounders, the increase in the relative risk of the composite endpoint across quintiles of hsTnT appeared similar in men and women (Figure 2). Conclusions: In the BARI 2D trial, women have lower baseline hsTnT concentrations, but higher absolute risk of myocardial infarction, stroke, heart failure, or death for a given concentration of hsTnT. These data raise the question of whether sex-specific cutoffs for cardiac troponin T should be considered.

Research in brief

Risk of hip fractures in people with diabetes was examined in a meta-analysis of 21 observational studies, including more than 80 000 hip fractures and almost 7 million individuals. Fan and colleagues noted that diabetes doubled the risk of hip fractures in people relative to individuals without diabetes (relative risk [RR] 2·07, 95% CI 1·83–2·33); due to significant study heterogeneity (I2=97%; p<0·001), a random-effects model was used in the analysis. Compared with individuals without diabetes, type 1 diabetes was associated with a higher risk of hip fracture (RR 5·76, 95% CI 3·66–9·07; I2=91·8%, p<0·001) than type 2 diabetes (1·34, 1·19–1·51; I2=85·8%, p<0·001). Investigators for the BARI 2D trial have assessed use of high-sensitivity cardiac troponin T assays in individuals with stable ischaemic heart disease and type 2 diabetes (n=2285). The event rate of the composite endpoint of myocardial infarction, stroke, or death from cardiovascular causes at 5 years was 12·9% in individuals with a normal baseline troponin T (<14 ng/L) compared with 27·1% in individuals with abnormal troponin T concentrations (≥14 ng/L; adjusted hazard ratio [HR] 1·85, 95% CI 1·48–2·32; p<0·001). In participants with abnormal troponin T concentration at baseline, occurrence of the composite endpoint did not differ significantly between groups randomly allocated to prompt revascularisation or medical therapy (HR 0·96, 95% CI 0·74–1·25). Free thyroxine concentratons at the higher end of the normal range might be associated with increased risk of atrial fibrillation, according to results from the ongoing Rotterdam Study. In the longitudinal, prospective cohort study, researchers included 9166 adults followed up for a median of 6·8 years (IQR 3·9–10·9). During the study period, 403 new cases and 399 prevalent cases of atrial fibrillation were reported. In the normal range of free thyroxine, higher concentrations at baseline were associated with increased risk of atrial fibrillation during follow-up (highest quartile vs lowest quartile: adjusted HR 1·63, 95% CI 1·19–2·22; p for trend=0·005). Results from two preliminary studies have provided insight into the mechanism of action of metformin. In a phase 1 study of 20 healthy participants, Buse and colleagues showed that 1000 mg twice-daily delayed-release metformin—a formulation allowing delivery to the distal intestine—had about half the bioavailability of the currently used extended-release (2000 mg daily) and immediate-release (1000 mg twice-daily) preparations of the drug. In their 12-week, phase 2 dose-ranging study, the researchers randomly allocated 240 participants with type 2 diabetes to once-daily placebo, delayed-release metformin (600 mg, 800 mg, or 1000 mg), or unmasked extended-release metformin (1000 mg or 2000 mg). Delayed-release metformin (800 mg) resulted in significantly greater reductions in fasting plasma glucose from baseline to week 4 compared with placebo (p=0·006), with glucose lowering evident for all doses. Interestingly, delayed-release metformin seemed to have greater potency for glucose reduction than did the extended-release formulation. The authors noted that, “dissociation of the glycemic effect from plasma exposure with gut-restricted delayed-release metformin provides strong evidence for a predominantly lower bowel-mediated mechanism of metformin action”. Investigators for the TEAAM trial have assessed the effect of long-term testosterone use on markers of subclinical atherosclerosis in men aged 60 years or older with testosterone concentrations that were low or at the low end of the normal range. Researchers randomly allocated participants to daily placebo (n=152) or 7·5 g of 1% testosterone gel (n=156) for 36 months. The rate of change in both the distal right common carotid artery intima-media thickness and coronary artery calcium score did not differ significantly between the two groups (p=0·89 and p=0·54, respectively). Because the trial was designed to assess markers of atherosclerosis, the authors emphasised that their results, “should not be interpreted as establishing cardiovascular safety of testosterone use in older men”. Efficacy of liraglutide on weight loss in people with type 2 diabetes was assessed in the multicentre SCALE Diabetes trial. Individuals with a BMI of 27 or higher were randomly allocated to liraglutide 3·0 mg (n=423), liraglutide 1·8 mg (n=211), or placebo (n=212), and were provided with specific dietary and exercise advice. At week 56, weight decreased by 2·0% in the placebo group compared with 6·0% in the liraglutide 3·0 mg group (treatment difference −4·00%, 95% CI −5·10 to −2·90; p<0·001) and 4·7% in the 1·8 mg group (−2·71%, −4.00 to −1·42; p<0·001). Additionally, the proportions of participants achieving weight loss of 5% or more and 10% or more were significantly higher in the two treatment groups compared with placebo.

Comprehensive Cardiovascular Risk Factor Control Improves Survival: The BARI 2D Trial

BackgroundIt is unclear whether achieving multiple risk factor (RF) goals through protocol-guided intensive medical therapy is feasible or improves outcomes in type 2 diabetes mellitus. ObjectivesThis study sought to quantify the relationship between achieved RF goals in the BARI 2D (Bypass Angioplasty Investigation Revascularization 2 Diabetes) trial and cardiovascular events/survival. MethodsWe performed a nonrandomized analysis of survival/cardiovascular events and control of 6 RFs (no smoking, non–high-density lipoprotein cholesterol <130 mg/dl, triglycerides <150 mg/dl, blood pressure [systolic <130 mm Hg; diastolic <80 mm Hg], glycosylated hemoglobin <7%) in BARI 2D. Cox models with time-varying number of RFs in control were adjusted for baseline number of RFs in control, clinical characteristics, and trial randomization assignments. ResultsIn 2,265 patients (mean age 62 years, 29% women) followed up for 5 years, the mean ± SD number of RFs in control improved from 3.5 ± 1.4 at baseline to 4.2 ± 1.3 at 5 years (p < 0.0001). The number of RFs in control during the trial was strongly related to death (global p = 0.0010) and the composite of death, myocardial infarction, and stroke (global p = 0.0035) in fully adjusted models. Participants with 0 to 2 RFs in control during follow-up had a 2-fold higher risk of death (hazard ratio: 2.0; 95% confidence interval: 1.3 to 3.3; p = 0.0031) and a 1.7-fold higher risk of the composite endpoint (hazard ratio: 1.7; 95% confidence interval: 1.2 to 2.5; p = 0.0043), compared with those with 6 RFs in control. ConclusionsSimultaneous control of multiple RFs through protocol-guided intensive medical therapy is feasible and relates to cardiovascular morbidity and mortality in patients with coronary disease and type 2 diabetes mellitus. (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes [BARI 2D]; NCT00006305)

Abstract 172: Baseline Physical Activity and Clinical Outcomes in Patients with Diabetes Mellitus and Stable Ischemic Heart Disease: Analysis From BARI-2D Trial.

Introduction: We aimed to evaluate the differences in clinical outcomes among patients with DM and coronary heart disease according to their baseline physical activity status. Methods: We evaluated 2,343 patients with CHD and DM who underwent either prompt revascularization (PR) and intensive medical therapy (IMT) or IMT alone in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Patients were categorized according to their baseline physical activity status to sedentary, mild physical activity or moderate/strenuous activity. Primary end points were all cause mortality. Cox Regression analysis was used to evaluate the effects of baseline physical activity on all-cause-mortality. Results: Of 2,343 patients, 858 (37%) were able to achieve moderate/strenuous physical activity prior to randomization. Patients with sedentary life style and mild physical activity at baseline had worse survival compared to those with higher activity levels (Figure). In a Cox regression analysis, in patients randomized to IMT alone, there were no differences in mortality across physical activity levels. In the PR arm, sedentary and mild physical activity carried high risk of mortality compared to strenuous activity levels. Furthermore, patients in the low physical activity categories carried an increased risk of death if they were randomized to the insulin sensitizing arm of the trial. Conclusions: In this study, patients with DM and CHD, moderate/strenuous physical activity at baseline had improved survival compared to mild physical activity or sedentary life-style.