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Supplemental Digital Content is available in the text.With worsening epidemiological trends for both the incidence and prevalence of type 2 diabetes mellitus (T2DM) and heart failure (HF) worldwide, it is critical to implement optimal prevention and treatment strategies for patients with these comorbidities, either alone or concomitantly. Several guidelines and consensus statements have recommended glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter type 2 inhibitors as add-ons to lifestyle interventions with or without metformin in those at high atherosclerotic cardiovascular disease risk. However, these recommendations are either silent about HF or fail to differentiate between the prevention of HF in those at risk versus the treatment of individuals with manifest HF. Furthermore, these documents do not differentiate among those with different HF phenotypes. This distinction, even though important, may not be critical for sodium-glucose cotransporter type 2 inhibitors in view of the consistent data for benefit for both atherosclerotic cardiovascular disease– and HF-related outcomes that have emerged from the regulatory-mandated cardiovascular outcome trials for all sodium-glucose cotransporter type 2 inhibitors and the recent DAPA-HF trial (Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction)demonstrating the benefit of dapagliflozin on HF-related outcomes in patients with HF with reduced ejection fraction with or without T2DM. However, the distinction may be crucial for glucagon-like peptide-1 receptor agonists and other antihyperglycemic agents. Indeed, in several of the new statements, glucagon-like peptide-1 receptor agonists are suggested treatment not only for patients with T2DM and atherosclerotic cardiovascular disease, but also in those with manifest HF, despite a lack of evidence for the latter recommendation. Although glucagon-like peptide-1 receptor agonists may be appropriate to use in patients at risk for HF, mechanistic insights and observations from randomized trials suggest no clear benefit on HF-related outcomes and even uncertainty regarding the safety in those with HF with reduced ejection fraction. Conversely, theoretical rationales suggest that these agents may benefit patients with HF with preserved ejection fraction. Considering that millions of patients with T2DM have HF, these concerns have public health implications that necessitate the thoughtful use of these therapies. Achieving this aim will require dedicated trials with these drugs in both patients who have HF with reduced ejection fraction and HF with preserved ejection fraction with T2DM to assess their efficacy, safety, and risk-benefit profile.

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Responding to concerns about the potential for increased risk of adverse cardiovascular outcomes, specifically myocardial infarction, associated with certain glucose-lowering therapies, the US Food and Drug Administration and the Committee for Medicinal Products for Human Use of the European Medicines Agency issued guidance to the pharmaceutical industry in 2008. Glucose-lowering therapies were granted regulatory approval primarily from smaller studies that have demonstrated reductions in glycated hemoglobin concentration. Such studies were overall underpowered and of insufficient duration to show any effect on cardiovascular outcomes. The 2008 guidance aimed to ensure the cardiovascular safety of new glucose-lowering therapies to treat patients with type 2 diabetes mellitus. This resulted in a plethora of new cardiovascular outcome trials, most designed primarily as placebo-controlled noninferiority trials, but with many also powered for superiority. Several of these outcome trials demonstrated cardiovascular benefits of the newer agents, resulting in the first-ever cardiovascular protection indications for glucose-lowering therapies. Determining whether the guidance continues to have value in its current form is critically important as we move forward after the first decade of implementation. In February 2018, a think tank comprising representatives from academia, industry, and regulatory agencies convened to consider the guidance in light of the findings of the completed cardiovascular outcome trials. The group made several recommendations for future regulatory guidance and for cardiovascular outcome trials of glucose-lowering therapies. These recommendations include requiring only the 1.3 noninferiority margin for regulatory approval, conducting trials for longer durations, considering studying glucose-lowering therapies as first-line management of type 2 diabetes mellitus, considering heart failure or kidney outcomes within the primary outcome, considering head-to-head active comparator trials, increasing the diversity of patients enrolled, evaluating strategies to streamline registries and the study of unselected populations, and identifying ways to improve translation of trial results to general practice.

Following regulatory guidance set forth in 2008 by the US Food and Drug Administration for new drugs for type 2 diabetes mellitus, many large randomized, controlled trials have been conducted with the primary goal of assessing the safety of antihyperglycemic medications on the primary end point of major adverse cardiovascular events, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Heart failure (HF) was not specifically mentioned in the US Food and Drug Administration guidance and therefore it was not a focus of these studies when planned. Several trials subsequently showed the impact of antihyperglycemic drugs on HF outcomes, which were not originally specified as the primary end point of the trials. The most impressive finding has been the substantial and consistent risk reduction in HF hospitalization seen across 4 trials of sodium glucose cotransporter 2 inhibitors. However, to date, these results have not led to regulatory approval of any of these drugs for a HF indication or a recommendation for use by US HF guidelines. It is therefore important to explore to what extent persuasive treatment effects on nonprimary end points can be used to support regulatory claims and guideline recommendations. This topic was discussed by researchers, clinicians, industry sponsors, regulators, and representatives from professional societies, who convened on the US Food and Drug Administration campus on March 6, 2019. This report summarizes these discussions and the key takeaway messages from this meeting.

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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.

Introduction:Bidirectional associations between hypoglycemia and cardiovascular (CV) outcomes were evaluated in 2 CV outcome trials of the DPP-4 inhibitor, linagliptin.Methods:CARMELINA and CAROLINA trials evaluated CV outcomes with linagliptin vs placebo or glimepiride, respectively, in adults with type 2 DM at high CV ± kidney risk; of the 2, CARMELINA was longer duration/higher risk cohort. The primary outcome for both trials was CV death, myocardial infarction (MI), or stroke (3P-MACE), with heart failure (HHF) added to the primary outcome for the present analyses. Hypoglycemia was defined as plasma glucose <54 mg/dL; severe hypoglycemia defined as needing external help. Associations between the first hypoglycemic episode and subsequent CV events, and conversely, between non-fatal CV events (MI, stroke, HHF) and subsequent hypoglycemic episodes, were assessed using multivariable Cox proportional hazards models. Sensitivity analyses explored the risk of CV events within 60 days after each hypoglycemic episode.Results:In CARMELINA, there was an association between hypoglycemia and subsequent 3P-MACE + HHF (adjusted HR: 1.23; 95% CI 1.04-1.46), and between non-fatal CV events and subsequent hypoglycemia (adjusted HR: 1.39; 95% CI 1.06-1.83). In CAROLINA, there was no significant association between hypoglycemia and subsequent 3P-MACE + HHF (adjusted HR: 1.00; 95% CI 0.76-1.32), nor between non-fatal CV events and subsequent hypoglycemia (adjusted HR: 1.44; 95% CI 0.96-2.16) (Fig). In analyses of CV events occurring within 60 days after hypoglycemia, in both trials, there was either no association observed or too few events to analyze.Conclusion:The observed bidirectional associations between hypoglycemia and CV outcomes in CARMELINA and no significant associations in CAROLINA challenge the notion that hypoglycemia causes adverse CV events, but rather suggest that both hypoglycemia and CV events identify vulnerable patients at risk for both.

Background:RCTs studying the effect of sodium-glucose co-transporter 2 inhibitors (SGLT2i) on cardiovascular (CV) risk factors and outcomes have been underpowered to assess patients with overweight or obesity, thus presenting the need for a meta-analysis.Methods:Electronic databases were queried up till February 2022 for RCTs comparing SGLT2i with placebo in patients with overweight (BMI ≥25 kg/m2) or obesity (BMI ≥30 kg/m2) - irrespective of diabetes status - with a follow-up of ≥24 weeks. Meta-analyses were performed using the generic inverse variance technique and a random-effects model. Results are presented as weighted mean differences (WMD) for continuous outcomes, and hazard ratios (HR) for dichotomous outcomes. Outcomes studied were: (i) weight; (ii) systolic BP; (iii) diastolic BP; (iv) heart rate; (v) HDL-C; (vi) LDL-C; (vii) major adverse cardiac events (MACE), i.e., composite of CV death, non-fatal myocardial infarction (MI) and non-fatal stroke; (viii) composite of heart failure hospitalization and CV death (HFH/CV death); (ix) mortality; (x) MI; and (xi) stroke.Results:Seventeen RCTs (47,649 patients) were included. Compared with placebo, SGLT2i significantly reduced weight (WMD: -2.32 kg [-2.77, -1.88]), HbA1c (WMD: -0.79 % [-0.98, - 0.61]) and systolic BP (WMD: -2.15 mm Hg [-3.08, - 1.22]). SGLT2i did not have a significant effect on diastolic BP (WMD: -0.55 mmHg [-1.51, 0.41]), heart rate (WMD: 0.08 bpm. [-0.21, 0.37]), HDL-C (WMD: 1.62 mmol l-1[-0.21, 3.45]) or LDL-C (WMD: 0.53 mmol l-1[-0.88, 1.94]). Amongst CV outcomes, SGLT2i reduced the risk of MACE (HR: 0.90 [0.81, 0.99]), HFH/CV death (HR: 0.82 [0.75, 0.90]), and mortality (HR: 0.85 [0.77, 0.94]). No effect was noted on stroke (HR: 0.99 [0.85, 1.26]) or MI (HR: 0.89 [0.77, 1.02]).Conclusions:In patients with overweight or obesity, SGLT2i produce a modest but significant reduction in weight, systolic BP and HbA1c. SGLT2i may also reduce the risk of MACE, HFH/CV death, and mortality.

Introduction:Given the potential link between non-alcoholic fatty liver disease and increased cardiovascular (CV) risk, the associations between markers of hepatic steatosis/fibrosis with CV and kidney outcomes were explored.Methods:These post hoc analyses were conducted on data from the VERTIS CV trial that randomized patients with type 2 diabetes (T2D) and atherosclerotic CV disease (ASCVD) to ertugliflozin 5 or 15 mg or placebo, with all randomized groups pooled for the present analyses. The presence of hepatic steatosis was estimated by hepatic steatosis index (HSI; 8 х ALT/AST + BMI + 2 if T2D + 2 if female); and for hepatic fibrosis, fibrosis-4 score (FIB-4; [age х AST]/[platelets count х √ALT]). Patients were divided into quartiles (Q1 to Q4) according to baseline for each score. CV and kidney outcomes (CV death/myocardial infarction/stroke [MACE]; hospitalization for heart failure [HHF]/CV death; CV death; HHF; and sustained ≥40% decrease in eGFR from baseline/dialysis or transplantation/kidney death) were stratified by baseline HSI and FIB-4 quartiles.Results:Among 8246 patients, the mean age was 64.4 years, mean BMI 32.0 kg/m2, mean HSI 44.0, and mean FIB-4 score 1.34. Event rates of MACE, HHF/CV death, CV death, and HHF increased with FIB-4 quartile (Fig A). The hazard ratios (HR, 95% CI) of events by FIB-4 quartile (Q4 vs Q1) were 1.48 (1.25, 1.76), 2.0 (1.63, 2.51), 1.85 (1.45, 2.36), and 2.94 (1.98, 4.37) for MACE, HHF/CV death, CV death, and HHF, respectively. The kidney composite did not differ across FIB-4 quartiles. CV and kidney outcomes did not differ across HSI quartiles, except for higher incidence of HHF in the upper HSI quartile (HR [95% CI], Q4 vs Q1: 1.52 [1.07, 2.17]) (Fig B).Conclusion:In VERTIS CV, baseline fibrosis scores were associated with incident CV events in patients with T2D and ASCVD, despite the upper cutoff excluding advanced fibrosis. Steatosis only correlated with HHF, and neither measure was associated with the composite kidney outcome.

Background:Recent guidelines have outlined echo markers of diastolic dysfunction (DD); evidence is limited for their prognostic value for hospitalization for heart failure (HHF) in overweight and obese pts.Methods:CAMELLIA-TIMI 61 was a randomized placebo-controlled trial of the weight loss agent lorcaserin in 12,000 pts with BMI ≥27 with or at risk for CV disease (median follow-up, 3.3 yrs). Echo with core lab interpretation was performed on a subset of pts. Established DD parameters were measured, including the ratio of the peak early transmitral diastolic flow velocity over the early diastolic mitral annulus velocity (average E/e’), left atrium volume index (LAVi), and tricuspid regurgitation jet velocity (TRV). These were analyzed continuously, using the standard cutpoints of >14, >34 mL/m2, and >2.8 m/s, respectively, and separately to determine the optimal cutpoints. The primary outcome for this analysis was HHF.Results:In 3,972 pts with baseline ejection fraction ≥50%, all 3 variables on a continuous scale predicted increased risk of HHF; using standard cutpoints, only E/e’>14 remained independently associated with HHF after adjustment for the other 2 echo parameters and clinical variables (Panel A). In an analysis of optimal cutpoints in these overweight and obese pts, >13 was optimal for E/e’, >2.5 m/s for TRV, and >58 mL/m2for LAVi. In a model with all 3 echo parameters, all remained significant predictors of HHF. After incorporation of clinical variables, E/e’ (HR 2.15, 95%CI 1.24-3.72) and LAVi (HR 2.41, 1.33-4.36) remained independent predictors of HHF (Panel A). Rates of HHF were 0.6, 3.3, and 10.1% (p-trend<0.0001) in pts with none, one, or both measures of DD (Panel B).Conclusions:Several echocardiographic markers of diastolic dysfunction used in current guidelines predict increased risk of HHF events in the understudied obese and overweight population. A higher LAVi (> 58 ml/m2) cutpoint should be considered in these pts to prognosticate risk of HHF.

Introduction:The WATCH-DM score can predict risk of heart failure (HF) in patients with diabetes.Hypothesis:Addition of natriuretic peptide (NP) levels will improve WATCH-DM performance in individuals with dysglycemia.Methods:Adults with diabetes/pre-diabetes free of HF at baseline from 4 cohort studies (ARIC, CHS, FHS, and MESA) were included. The integer- [WATCH-DM(i)] and machine learning-based [WATCH-DM(ml)] scores were used to estimate the 5-year risk of incident HF. Discrimination was assessed by Harrell's concordance index (C-index) and calibration by the Greenwood-Nam-D'Agostino (GND) statistic. Improvement in model performance with the addition of NP-levels was assessed by C-index, Brier score, and continuous net reclassification improvement (NRI).Results:Of the 8,938 participants included, 3,554 (39.8%) had diabetes and 432 (4.8%) developed HF within 5-years. Among 5,384 (60.2%) participants with pre-diabetes, 647 (12.0%) developed incident HF. The WATCH-DM(ml) and (i) scores demonstrated high discrimination for predicting HF risk in diabetes (C-indices=0.76 and 0.69), pre-diabetes (0.83 and 0.72), and overall cohort (0.80 and 0.71), respectively, with no evidence of miscalibration (GND=P >0.10). A greater improvement in C-index was observed with the addition of NP-levels at lower WATCH-DM(i) scores with degradation of risk discrimination at higher scores (Fig. A). Calibration was also improved with addition of NP-levels at lower compared to higher WATCH-DM(i) scores (Fig. B). A greater improvement in reclassification was observed by combing WATCH-DM(i) score with selected NP-levels assessment in low (score<13) vs. high-risk (≥13) participants (NRI=0.45 vs. 0.17; p-value<0.001).Conclusions:The WATCH-DM risk score can accurately predict incident HF risk in community-based individuals with dysglycemia. The addition of NP-levels improves risk prediction among adults with low/intermediate but not high HF risk.

Background:Evidence from large randomized clinical trials supports the benefit of SGLT2is to improve cardiovascular and kidney outcomes in patients with type 2 diabetes mellitus (T2DM). In light of this evidence, prescription patterns of SGLT2i among US Medicare beneficiaries were evaluated.Methods:Antihyperglycemic medication prescribers were based on metformin prescribing in national Medicare part D prescriber data. The proportion of clinicians prescribing SGLT2i was assessed overall and across specialties in 2018, with changes assessed from 2014 to 2018. The relative use of SGLT2i was compared with other second-line antihyperglycemic medication classes, sulfonylureas and dipeptidyl peptidase-4 inhibitors (DPP4is), without known CV benefits.Results:Among the 232,523 unique clinicians who prescribed metformin for Medicare beneficiaries in 2018, 45,255 (19.5%) prescribed SGLT2i - varying from 72% of endocrinologists to 14% of cardiologists. Among clinicians who prescribed both sulfonylureas and SGLT2i, SGLT2i were prescribed to 33% (IQR 18%, 67%) the number prescribed sulfonylureas. Of 118,091 metformin-prescribing clinicians who also prescribed DPP4i, 39,511 (33.5%) used SGLT2i, with a median 50% SGLT2i prescription volume relative to DPP4i (IQR 33, 100). Between 2014-2018, the number of unique clinicians prescribing SGLT2i increased from 5-fold, from 9,048 in 2014 to 45,255 in 2018, and proportionate utilization of SGLT2i per prescriber relative to sulfonylureas also increased from 19% in 2014 to 33% in 2018 (P-trend <0.001).Conclusions:A vast majority of diabetes-treating clinicians did not prescribe SGLT2i to Medicare beneficiaries as recently as 2018. Moreover, prescriptions of sulfonylureas and DPP4is, which have no known cardiac or kidney benefits, were 3 and 2 times more frequent, respectively, than those of SGLT2is. These findings highlight opportunities to improve care and outcomes for patients with T2DM.

Introduction:Sodium-glucose cotransporter-2 (SGLT2) inhibitors have well-documented cardioprotective effects in broad groups of patients with type 2 diabetes mellitus (T2DM) but are underused, in part due to high cost. Individualized prediction of the magnitude of cardiovascular risk reduction may allow more targeted use.Hypothesis:A machine learning decision support tool can predict ASCVD effect of canagliflozin therapy in T2DM based on each patient’s unique phenotypic profile.Methods:We constructed a topological representation of the Canagliflozin Cardiovascular Assessment Study (CANVAS) using 75 baseline variables collected from 4327 patients with T2DM randomly assigned to canagliflozin (n=2886) or placebo (n=1441). Within each patient’s 5% topological neighborhood, we calculated age- and sex-adjusted risk estimates for major adverse cardiovascular events (MACE: cardiovascular death, myocardial infarction, stroke). An extreme gradient boosting algorithm was trained to predict the personalized MACE effect of canagliflozin using features consistently associated with benefit in topological analyses and was validated in the independent CANVAS-R trial (n=5808, randomized 1:1 to canagliflozin or placebo).Results:In CANVAS (mean age 60.9±8.1 years, 33.9% women) 1605 (37.1%) patients had a neighborhood hazard ratio lower (more protective) than the overall effect estimate of 0.86 for the primary composite outcome of time to MACE (A). A 15-variable tool, INSIGHT, was developed in CANVAS (B), and subsequently tested in CANVAS-R (mean age 62.4±8.4 years, 2164 (37.3%) women) where it identified patient phenotypes with higher MACE benefit of canagliflozin (adj. HR 0.60 [95% CI: 0.41-0.89] (C) versus 0.99 [95% CI: 0.76-1.29] (D); P-value for interaction=0.04).Conclusions:We present an evidence-based, machine learning-guided algorithm to personalize the prescription of SGLT2 inhibitors for cardiovascular benefit in patients with T2DM.

Introduction:Dapagliflozin (DAPA-CKD) and finerenone (FIDELIO-DKD) have shown to improve renal and cardiovascular (CV) outcomes in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD).Hypothesis:We hypothesize individuals in a community-cohort who meet trial criteria will have higher rates of adverse outcomes.Methods:Adults with CKD from the Chronic Renal Insufficiency Cohort (CRIC) study were included. The inclusion criteria from each trial were applied to participants with T2D. Differences in characteristics and composite kidney and CV outcomes were assessed between trial eligibility groups. The estimated number of events prevented (NEP) over 3 years were calculated based on relative risk reduction estimates.Results:Among 2816 participants (mean [SD] age 62 [10], 41% female, 48% Black), 1545 (54.9%), 1458 (51.8%), and 1314 (46.7%) met DAPA-CKD, FIDELIO-DKD, and both inclusion criteria, respectively. Participants who met DAPA-CKD but not FIDELIO-DKD enrollment criteria were more likely to be Black and have higher CV, T2D, and kidney disease severity. Participants who met DAPA-CKD criteria (vs. ineligible) had higher rates of composite kidney (17.6% vs. 14.6%; p=0.006) and CV (15.5% vs. 12.6%; p=0.03) outcomes. Conversely, FIDELIO-DKD eligible participants had lower incidence of composite kidney outcomes (12.6% vs. 19.4%; p<0.001) and no differences in CV outcomes (14.2 vs. 14.2%; p=0.99). The estimated NEP per 1000 patients with dapagliflozin was 60 and 43 for kidney and CV outcomes, respectively, compared with 21 and 19 for finerenone (Fig). Notable differences in NEP were observed between races for dapagliflozin but not finerenone treatment, with Black patients having significantly higher kidney and CV NEP (Fig).Conclusions:In a community-based registry of CKD patients, approximately half of patients would be eligible for dapagliflozin or finerenone. The estimated NEP was higher with dapagliflozin compared to finerenone.

Background:Evidence-based therapies for cardiovascular risk reduction are generally underused in patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD). While patterns of preventive care have been documented in selected populations, insight into the contemporary use of these evidence-based therapies in broader US populations is lacking.Methods:Data were obtained from 12 health systems with data marts linked to the National Patient-Centered Clinical Research Network. Patients with T2DM and established ASCVD (coronary artery disease, cerebrovascular disease and peripheral artery disease) with a healthcare encounter in 2018 were identified and their lipid, blood pressure and glucose-lowering therapies evaluated. Descriptive analyses were performed on patient characteristics by prescription of any of the following key evidence-based therapies: high-intensity statin, angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB), and sodium glucose co-transporter-2 inhibitors (SGLT-2i) or glucagon-like peptide-1 receptor agonist (GLP-1RA).Results:The overall cohort comprised 324,706 patients with mean age 68.2 years, 44.4% were female, 36.0% non-white and 12.8% Latinx. In the prior year, 8.7% visited an endocrinologist, while 26.4% visited a cardiologist and 74.8% visited a primary care physician. Overall, 58.6% were prescribed a statin (26.8% were on a high-intensity formulation), 45.5% were prescribed an ACEi or ARB, and 3.9% were prescribed a GLP-1RA and 2.8% an SGLT-2i. Overall, 4.6% were prescribed all three therapies and 42.5% were prescribed none. Those prescribed either an SGLT-2i or a GLP-1RA were younger, more likely to be privately insured, have fewer comorbidities, more complex T2DM and have seen an endocrinologist.Conclusions:In this large, US national cohort of patients with T2DM and ASCVD, fewer than 1 in 20 patients were prescribed all 3 of a high intensity statin, either an ACEi or ARB and either an SGLT-2i or a GLP-1RA. Multifaceted interventions are needed to overcome barriers to the implementation of evidence-based therapies and their suboptimal use, as confirmed in this large, representative cohort of patients in the United States.

Background:Data from VERTIS CV (NCT01986881) were analyzed to study the effect of ertugliflozin on kidney outcomes in patients with and without baseline evidence of HF.Methods:Patients with type 2 diabetes mellitus and ASCVD were randomized (1:1:1) to ertugliflozin 5 or 15 mg (both doses pooled for analyses) or placebo. Subgroups were defined by baseline history of HF or a pre-randomization left ventricular ejection fraction (EF) ≤45%. eGFR over time, total 5-year eGFR slopes and Cox proportional hazards for time to first event of a kidney composite of sustained ≥40% decrease from baseline eGFR, chronic kidney replacement therapy, or kidney death were assessed.Results:At baseline, 2439 (29.6%) had a history of HF or EF ≤45% (HF) and 5807 (70.4%) had no evidence of HF (no HF). Compared with placebo, ertugliflozin treatment resulted in a slower rate of eGFR decline in both subgroups; total placebo-adjusted 5-year eGFR slope (mL/min/1.73 m2/year [95% CI]): 0.96 (0.67, 1.24) and 0.95 (0.76, 1,14) for the HF and no HF subgroups, respectively (Figure 1). The HF subgroup had a higher event rate for the composite kidney outcome than the no HF subgroup. Hazard ratios (95% CI) for ertugliflozin for reducing the risk of the composite kidney outcome did not differ significantly across the two subgroups; 0.53 (0.33, 0.84) and 0.76 (0.53, 1.08) for the HF and no HF subgroups, respectively (Pinteraction=0.22) (Figure 2).Conclusion:In VERTIS CV, patients with HF at baseline had a notably faster rate of eGFR decline that is unlikely to be explained by the slightly lower baseline eGFR in that group. The effects of ertugliflozin on kidney outcomes did not differ between the two groups stratified by baseline HF.

Introduction:Phenomapping can be used to identify subgroups of patients with similar risk factor profiles; however, there is no widely accepted clustering method. We compared 3 phenomapping strategies to identify groups of individuals with diabetes mellitus (DM) and high cardiovascular disease (CVD) risk.Methods:Participants with DM and no baseline CVD from the ACCORD trial (N = 6591) were included in this study. Among 45 mixed data variables, we used an informed variable selection method with optimization of the Wald index to select the top 20 covariates associated with survival. Gaussian mixture models (GMM), Latent Class Analysis (LCA), and finite mixture model-based clustering (FMM) were performed to identify mutually exclusive phenogroups. Bayesian information criterion (BIC) and Dunn index were calculated for each method and compared. The primary composite endpoint was cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke.Results:FMM clustering with 3 phenogroups was the optimal clustering strategy as determined by the lowest BIC and highest Dunn index (Figs A-B). Phenogroup 1 had a higher burden of comorbidities and DM complications; phenogroup 2 were older with intermediate CV comorbidity burden, but lowest complications from DM; and phenogroup 3, the largest group, had a lower prevalence of CV-related comorbidities. In adjusted Cox models, over 4.9 years median follow-up, phenogroup 1 and 2 participants (vs. phenogroup 3) had a significantly higher risk of primary composite endpoint (Fig C). In Cox analysis, when group membership was added to 10 optimal predictors of primary composite endpoint, the C-index improved from 0.68 to 0.70 (P= 0.02). Similar risk patterns were also observed in an external cohort (Look AHEAD trial, N = 4211) with the highest risk of adverse outcome seen in phenogroup 1 (Fig D).Conclusion:Semi-supervised clustering using FMM efficiently identifies phenogroups of patients with DM with distinct clinical characteristics and CVD risk.

Introduction:Type 2 Diabetes (T2DM) is associated with higher risk for HF. The contributions of baseline measures of and changes in fitness (CRF) toward HF risk in T2DM is not well-established.Methods:Participants of the Look AHEAD trial without prevalent HF randomized to the intensive lifestyle intervention (ILI) vs. usual care arms were included. Incident HF hospitalization and its subtypes [HF with preserved ejection fraction (EF>= 50%, HFpEF) & HF with preserved ejection fraction (EF < 50%, HFrEF)] were adjudicated through the end of 2014 using a validated approach. The associations of baseline CRF estimated from a maximal treadmill test and changes in CRF (from baseline to year 4) with risk of HF and its subtypes were evaluated using adjusted Cox models.Results:Among the 5,109 study participants, there was no significant difference in the risk of HF (n = 257 events) between the ILI vs. usual care groups [HR (95% CI) = 0.96 (0.75 - 1.23)] over 12.4 years follow up. In adjusted analysis, the risk of HF was 39% and 62% lower among moderate fit [Tertile 2] and high fit [Tertile 3] groups, respectively [vs. low fit (Tertile 1), Table]. Among HF subtypes, the risk of HFpEF was 40% lower in moderate fit and 77% lower in the high fit groups (vs. low fit). In contrast, baseline CRF was not associated with risk of HFrEF after adjustment for potential confounders (Table). BMI was also not associated with risk of HF after adjustment for CV risk factors. Among participants with repeat CRF testing (n = 3,902), improvements in CRF and weight loss over 4-year follow-up was significantly associated with lower risk of HF [HR (95% CI) per 10% increase in CRF = 0.90 (0.82 to 0.99), per 10% decrease in BMI = 0.80 (0.69 to 0.94)].Conclusion:Higher baseline CRF is independently associated with lower risk of HF, particularly HFpEF, among individuals with T2DM. Improvements in CRF and weight loss can significantly lower risk of HF in this high-risk population. However, the ILI implemented in the LookAHEAD trial did not modify the risk of HF among the study participants.