Search

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Introduction:Circulating cardiovascular (CV) biomarkers, including N-terminal pro-B type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT), are associated with risk of heart failure (HF) events in patients (pts) with type 2 diabetes (T2D). Less is known about the prognostic significance of changes in these biomarkers over time or the early effects of the SGLT2i dapagliflozin (dapa) on these markers.Methods:DECLARE-TIMI 58 was a randomized, placebo-controlled trial of dapa in 17,160 pts with T2D (median f/u = 4.2y). NT-proBNP & hsTnT (Roche) were measured at baseline & 6 mo. The outcome of interest was CV death (CVD) or hosp for HF (HHF). Outcome analyses were performed from a landmark of the 6-mo study visit with pts categorized by change in each biomarker over the first 6 mo. Hazard ratios were adjusted for baseline biomarker value, randomized treatment, age, sex, race, smoking, eGFR, prior HF, BMI, T2D duration, insulin use, CAD, prior MI, ischemic stroke, PAD, dyslipidemia, & hypertension. Linear mixed models were used to assess the effect of dapa on log-transformed NT-proBNP & hsTnT.Results:Serial NT-proBNP & hsTnT values were available in 13,459 pts (78%). Among pts allocated to placebo (n=6,698), NT-proBNP was more dynamic than hsTnT (≥20% change from baseline in 71% vs. 33% of pts; p<0.001). In the full cohort, independent of randomized treatment, there was a stepwise graded relationship between change in NT-proBNP & hsTnT and risk of CVD/HHF, whereby increases in either biomarker were associated with higher risk and decreases in either biomarker were associated with lower risk (p-trend for adj-HR <0.001 for each). Considered together, changes in the 2 markers were complementary (Fig; p<0.001). Dapa significantly reduced NT-proBNP (relative LS mean change, -6% [-4% to -8%]; p<0.001) but not hsTnT (0% [-1% to +1%]; p=0.92) over 6 mo.Conclusions:Early changes in hsTnT & NT-proBNP are associated with subsequent risk of CVD/HHF in pts with T2D.

Background:In the DECLARE-TIMI 58 trial, involving patients with type 2 diabetes at high cardiovascular (CV) risk, dapagliflozin reduced the risk for heart failure hospitalization and adverse kidney outcomes, compared to placebo. Whether dapagliflozin lowers the risks for the broader outcome of adverse event (AE)-related hospital admissions is unknown.Methods:The DECLARE-TIMI 58 trial randomized 17,160 subjects with type 2 diabetes and a high risk for or established CV disease, to receive dapagliflozin or placebo (1:1). Dapagliflozin effect on AE-related hospital admissions was assessed overall and by baseline cardiovascular and kidney subgroups. Investigator reported system organ class classification was used to evaluate dapagliflozin's effects on admissions due to different etiologies.Results:Over a median follow up of 4.2 years, dapagliflozin reduced the risk of AE-related hospital admissions by 11% (32.4% vs. 35.4% of participants, HR 0.89 [95% CI 0.85, 0.94]; p<0.0001). The reduction in AE-related hospital admissions was consistent across baseline cardiovascular and kidney subgroups (p-interaction≥0.30) (Figure). Dapagliflozin reduced the risk for admissions due to cardiac disorders (HR 0.91 [95% CI 0.84,0.995] p=0.0387), renal or urinary disorders (0.61 [0.49, 0.77] p<0.0001), and other non-cardiac, non-renal etiologies (0.89 [0.84,0.95] p=0.0001).Conclusion:Dapagliflozin reduced the risk for AE-related hospital admissions, including non-cardiac and non-renal hospitalizations, in patients with type 2 diabetes. These findings have implications for patients' quality of life and overall type 2 diabetes-attributed healthcare burden.

Introduction:SGLT2 inhibitors reduce cardiovascular (CV) risk in a broad range of patients including those with and without type 2 diabetes mellitus (DM). In addition, non-glycemic effects modify parameters that define metabolic syndrome (MetS) such as weight, BP, and lipid profile. In this context, we investigated the effects of dapagliflozin on key components of MetS and the association with outcomes.Methods:17,160 patients with DM were randomized to dapagliflozin or placebo in DECLARE-TIMI 58. Since all had DM, MetS was classified using a modification of IDF criteria requiring BMI ≥30 kg/m2and ≥1 of the following: triglycerides ≥150 mg/dL, HDL-C <40 in men or <50 mg/dL in women, SBP ≥130 or DBP ≥85 mmHg. Classification of MetS and its subcomponents were tracked at baseline and follow-up visits (6-48 months). An analysis adjusted for baseline characteristics and treatment was performed to assess the association of MetS with key outcomes.Results:At baseline, 53% had MetS. On adjusted analysis, MetS was predictive of CV death or hospitalization for heart failure (CVD/HHF) (HR 1.28, 95%CI 1.11-1.47, p<0.001), HHF (HR 1.62, 95%CI 1.33-1.97, p<0.001), and MI (HR 1.22, 95%CI 1.05-1.4, p=0.008). From 6 to 48 months, there was a lower prevalence of MetS in the dapagliflozin arm (47.9% vs. 52.5%, p<0.001, Figure 1), as well as lower prevalence of BMI ≥30 kg/m2(54.9% vs. 58.0%), low HDL-C (38.7% vs. 42.6%), and elevated BP (58.2% vs. 65.7%) with p<0.001 for each. In the dapagliflozin arm, there were lower odds of progression to MetS (10.5% vs. 13.5%; OR 0.76, 95%CI 0.64-0.89, p<0.001) and, in those with MetS at baseline, higher odds of regression (24.6% vs. 18.3%; OR 1.45, 95%CI 1.29-1.64, p<0.001) at 48 months.Conclusions:The presence of MetS is prognostically important in patients with DM. Dapagliflozin led to significant early and sustained changes in the likelihood of MetS.

Introduction:GWAS have identified SNPs associated with an increased risk of peripheral artery disease (PAD). We sought to compare the performance of a genetic risk score (GRS) comprised of these SNPs with established clinical risk factors to predict PAD and acute limb ischemia (ALI) across five RCTs in cardiometabolic disease. Given high prevalence of coronary artery disease (CAD) in patients with PAD, we also evaluated the performance of the GRS for incident myocardial infarction (MI).Methods:Pts from the ENGAGE AF-TIMI 48, SOLID-TIMI 52, SAVOR-TIMI 53, PEGASUS-TIMI 54, and FOURIER trials were included in this analysis. ALI and MI were adjudicated by a blinded CEC comprised of vascular medicine specialists and cardiologists. A previously validated GRS (Nature Medicine2019) of 19 SNPs associated with PAD was calculated for each pt. ORs for PAD were calculated across genetic risk groups. HRs adjusted for clinical risk factors were calculated for ALI and incident MI.Results:Of 51,729 total pts included in this analysis, 5,149 (10%) had PAD at baseline. Pts in the top 20% of GRS had 47% higher odds of having PAD compared with those in the bottom 20% (adj OR 1.47, 95% CI 1.33-1.62; p<0.001). The magnitude of risk for PAD conferred by high GRS was similar to many established clinical risk factors (Figure). A total of 91 ALI events occurred over a median follow-up of 2.4 years. Pts in the top 20% of GRS were at 63% increased risk for ALI compared with those in the bottom 80% (adj HR 1.63, 95% CI 1.04-2.56.; p=0.03), consistent in those with and without PAD (p-interaction 0.85). The PAD GRS was also associated with incident MI (n=2323), with pts in the top 20% of GRS at 42% increased risk compared with the bottom 80% (adj HR 1.42, 95% CI 1.36-1.49; p<0.001).Conclusions:A 19-SNP GRS was a strong independent predictor of PAD and ALI in patients with cardiometabolic disease. The PAD GRS also predicted MI, supporting overlapping biological mechanisms for atherosclerosis across vascular beds.

Introduction:Atrial fibrillation (AF) and atrial flutter (AFL) are associated with diabetes and its comorbidities including hypertension, obesity, and heart failure (HF). Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to lower blood pressure, reduce weight, have salutary effects on left ventricular remodeling and reduce hospitalization for HF and cardiovascular death in patients with type 2 diabetes (T2D). We therefore hypothesized that SGLT2i may reduce the risk of AF/AFL.Methods:DECLARE-TIMI 58 studied the efficacy and safety of the SGLT2i dapagliflozin in 17160 patients with T2D and either multiple risk factors for (MRF, n=10186) or known atherosclerotic cardiovascular disease (ASCVD, n=6974). Here, we explore the effect of dapagliflozin on the first and total number of AF/AFL events using Cox and negative binomial models, respectively. AF events were identified using a MedDRA preferred term search (?Atrial Fibrillation?, ?Atrial Flutter?) in the safety database.Results:Dapagliflozin reduced the risk of incident AF/AFL by 19% (264 versus 325 events; hazard ratio 0.81, 95% CI 0.68 to 0.95, P=0.009, Fig A). The reduction in AF/AFL events was consistent regardless of presence or absence of a history of AF/AFL at baseline (Prior AF/AFL (n=1116): HR 0.79, 95% CI 0.58 to 1.09, No AF/AFL: HR 0.81, 95% CI 0.67 to 0.98; P-INT 0.89). Similarly, presence of ASCVD (HR 0.78, 95% CI 0.62 to 0.99) versus MRF (HR 0.83, 95% CI 0.66 to 1.04; P-INT 0.72), or a history of HF (HF: HR 0.78, 95% CI 0.55 to 1.11, No HF: HR 0.81, 95% CI 0.68 to 0.97; P-INT 0.88) did not modify the reduction in AF/AFL events observed with dapagliflozin. Dapagliflozin also reduced the total number of AF/AFL events (337 versus 432; rate ratio 0.77, 95% CI 0.64 to 0.92, P=0.005; Fig B).Conclusions:Dapagliflozin appears to reduce both incident AF/AFL as well as the total number of AF/AFL events in patients with T2D. This effect was consistent regardless of the patients? prior history of AF, ASCVD, or HF.

Introduction:Dapagliflozin reduced the risk of the composite of cardiovascular death or hospitalization for heart failure (CVD/HHF) in patients (pts) with type 2 diabetes (T2D) in DECLARE-TIMI 58. We hypothesized that cardiac biomarkers may help to identify pts who are at higher baseline risk and thus may benefit more from treatment with SGLT2i.Aim:To evaluate the association of baseline hsTnT and NT-proBNP levels with CVD/HHF and with the magnitude of benefit with dapagliflozin.Methods:This was a prespecified biomarker study from DECLARETIMI 58, a randomized, double-blind, placebo-controlled CV outcomes trial of dapagliflozin in pts with. Baseline NT-proBNP and hsTnT levels were measured in the TIMI Biomarker Core Laboratory in 14,565 pts (median follow-up 4.2 y). Patients were stratified by baseline biomarker levels. Relative risk ratios using hazard ratios and absolute risk reductions using Kaplan-Meier event rates at 4 years with dapagliflozin were calculated for CVD/HHF within biomarker quartiles.Results:The median baseline NT-proBNP and hsTnT levels were 75 pg/mL (IQR 35-165) and 10.2 pg/mL (IQR 6.9-15.5), respectively. Patients with higher levels of NT-proBNP and hsTnT had higher KM event rates of CVD/HHF (Q4 vs Q1: NT-proBNP: 13.7% vs 1.0%; hsTnT: 11.8% vs 1.4%; P-trend <0.001). Dapagliflozin consistently reduced the relative risk of CVD/HHF regardless of baseline NT-proBNP (P INT 0.72) or hsTnT quartiles (P INT 0.93). However, given their higher baseline risk, pts with elevated levels of NT-proBNP and/or hsTnT tended to derive even greater absolute risk reduction with dapagliflozin [ARR in Q4 for NT-proBNP 2.9% (NNT 35); hsTnT 2.4% (NNT 42)] [Figure].Conclusions:Patients with higher NT-proBNP or hsTnT levels are at increased risk of CV death and HHF. Dapagliflozin reduced the risk of CV death/HHF irrespective of NT-proBNP and hsTnT levels, with greater absolute risk reductions seen in pts with higher baseline biomarker levels.

Introduction:Sodium glucose transporter 2 inhibitors (SGLT2i) reduce the risk of major adverse cardiovascular events (MACE), including myocardial infarction (MI), in patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD). In DECLARE-TIMI 58, this benefit was seen in patients with ASCVD and particularly in those ones with prior MI. The effect of SGLT2i in reducing MIs of different types and sizes has not previously been reported.Hypothesis:In patients with T2DM and prior MI, dapagliflozin consistently reduces recurrent MI events across a range of infarct types & sizes.Methods:This was a pre-specified sub-analysis from DECLARE-TIMI 58, which randomized 17,160 patients with T2DM to dapagliflozin 10 mg vs. placebo, of whom, 3584 had a history of prior MI at enrollment. All MI events were prospectively adjudicated and classified according to: (1) Universal Definition types 1-5, (2) the presenting electrocardiogram (STEMI vs. NSTEMI), and (3) size based on peak troponin [as multiples of the upper limit of normal (ULN)]. Cox proportional hazards model was used to generate HR and 95 % CI.Results:From the total incident MIs (489) in patients with prior MI from DECLARE-TIMI 58, 316 (65%) were type 1 MIs and 403 (82%) were NSTEMI. From those with biomarkers available (456), 241 (53%) had peak troponin ? 10 X ULN. Besides reducing recurrent MI (HR 0.78; 95 % CI 0.63-0.95; p = 0.016), dapagliflozin appeared to favorably affect the risk of both type 1 (HR 0.80; 95 % CI 0.63-1.02) and type 2 (HR 0.64; 95 % CI 0.42-0.97) MIs. There also appeared to be a favorable reduction across all ranges of infarct sizes based on peak troponin (Figure).Conclusions:In patients with T2DM and prior MI, dapagliflozin consistently reduced recurrent MI across the spectrum of different infarct sizes and types, including those ones caused by a myocardial oxygen supply/demand mismatch. The mechanisms that explain reductions in MI with SGLT2i remain to be determined.

Introduction:Women remain underrepresented in clinical trials and at high risk for CV events in type 2 DM (T2DM). The SGLT-2 inhibitor dapagliflozin (DAPA) reduces CV death or HF hospitalizations (CVD/HHF) in T2DM, but the relative benefit in women versus men is undefined.Methods:DECLARE-TIMI 58 randomized 17,160 patients with T2DM with or at risk for atherosclerotic disease to DAPA or placebo (median f/up 4.2y). The dual efficacy outcomes were the composite of CVD/HHF and CV death, MI or ischemic stroke (MACE). Cox models were stratified by sex. The prespecified renal-specific outcome was a ?40% drop in eGFR to <60 ml/min/1.73m2, new ESRD, or renal death. Reported safety events were those leading to drug discontinuation or serious adverse events (SAEs).Results:At baseline, women (n=6422, 37%) tended to be older, have a higher BMI, higher HbA1c and longer duration of T2DM than men, but were on fewer antihyperglycemic meds and less likely to have established CV disease. DAPA reduced CVD/HHF by 16% in women (HR 0.84, 0.66-1.07) and 17% in men (HR 0.83, 0.71-0.96; P int=0.90; Fig). The HRs for MACE with DAPA were similar in women (HR 0.93, 95% CI 0.77-1.12) and men (HR 0.93, 0.83-1.05; P int=0.99). Renal-specific events were reduced by 50% in women (HR 0.50, 0.35-0.70) and 45% in men (HR 0.55, 0.42-0.73; P int=0.64). Treatment emergent SAEs were less common in DAPA than placebo-treated patients in both women (29.3% vs 31.5%) and men (36.9% vs 39.0%; P int=0.78). Urinary tract infections were similar in DAPA vs placebo (women: 2.2% vs 2.1%; men: 1.0% vs 1.2%; P int=0.30), but genital infections were more common with DAPA in both women (1.0% vs 0.1%) and men (0.8% vs 0.1%; P int=0.93).Conclusions:Antihyperglycemic drugs are used less frequently in women than men, despite longer duration of DM and higher HbA1c. The SGLT-2 inhibitor DAPA offers comparable CV benefit and safety profiles in both women and men. These findings lend support to the use of SGLT-2 inhibitors in women with T2DM.

Background:Patients with diabetes have an increased risk of MI. The prognostic value of a genome-wide polygenic risk score (GPS) developed in the general population for CAD compared with traditional cardiovascular and metabolic risk factors in diabetic patients is unknown.Methods:We studied 6,764 diabetic patients without prior MI from the SAVOR-TIMI 53 trial. The 6.6 million SNP GPS was calculated using the genotype dosage for each allele, multiplied by its weight, and then summed across all variants. Genetic risk categories were defined as low (Q1), intermediate (Q2-4), and high risk (Q5). The primary endpoint was a composite of MI or coronary heart death (CHD). Median follow up was 2 yrs. Cox proportional hazard regression analysis was performed adjusting for age, sex, and principle components 1-4 (ancestry). Similar analyses were done for traditional cardiovascular risk factors and all covariates were entered into a multivariable model to assess their independent strength.Results:There were 156 patients who had an MI or CHD during the trial. Compared with patients at low genetic risk, patients with high genetic risk were at a >2-fold (HR 2.15, 95% CI 1.25-3.71, p=0.006) and patients with intermediate risk were at a 68% higher risk (HR 1.68 [1.03-2.72], p=0.036) of MI or CHD. Of traditional clinical risk factors, GFR <60 mL/min/1.73m2and UACR >30 mg/g were the strongest predictors with approximately 2-fold increased risk of MI or CHD (HR 2.05, 95% CI 1.47-2.86, p<0.0001 & HR 1.98, 95% CI 1.44-2.74, p<0.0001, respectively). In a multivariable regression model (Figure), elevated genetic risk remained an independent predictor of a coronary event on par or above traditional risk factors.Conclusion:In patients with diabetes without prior myocardial infarction, a polygenic risk score is an independent predictor of MI that has prognostic value beyond established risk features, with patients in the top 20% of the risk score having a nearly 2.5-fold higher risk of MI or CHD.