Investigating the Role of Sotagliflozin in Cardiovascular Event Management

Tofacitinib is a Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA) and has been investigated for psoriasis (PsO). This post hoc analysis examined baseline cardiovascular (CV) disease risk and its association with the occurrence of major adverse cardiovascular events (MACE) and malignancies in tofacitinib-treated patients with PsA and PsO. Included three phase III/long-term extension (LTE) PsA trials and seven phase II/phase III/LTE PsO trials of patients receiving ⩾ 1 dose of tofacitinib. Incidence rates (IRs: patients with events/100 patient-years) for MACE and malignancies (excluding non-melanoma skin cancer) were determined in subgroups according to history of atherosclerotic CV disease (ASCVD), baseline 10-year risk of ASCVD (in patients without history of ASCVD), and baseline metabolic syndrome (MetS). For patients with PsA (N = 783) and PsO (N = 3663), respectively, tofacitinib exposure was 2038 and 8950 patient-years (median duration: 3.0 and 2.4 years), and 40.9% and 32.7% had MetS. Excluding missing CV risk profile data, 51/773 (6.6%) and 144/3629 (4.0%) patients had history of ASCVD, and in patients without history of ASCVD, around 20.0% had intermediate/high baseline 10-year ASCVD risk. For PsA and PsO, IRs of MACE were greatest in those with history of ASCVD or high baseline 10-year ASCVD risk. For PsA, five of six patients with MACE had baseline MetS. Malignancy IRs in patients with PsA were greatest in those with intermediate/high baseline 10-year ASCVD risk. Of these, eight of nine patients with malignancies had baseline MetS. In the PsO cohort, IR of malignancies was notably greater with high versus low/borderline/intermediate baseline 10-year ASCVD risk. In tofacitinib-treated patients with PsA/PsO, increased ASCVD risk and baseline MetS were associated with higher IRs for MACE and malignancies. Our results support assessing CV risk in patients with PsA/PsO and suggest enhanced cancer monitoring in those with increased ASCVD risk. NCT01877668/NCT01882439/NCT01976364/NCT00678210/NCT01710046/NCT01241591/NCT01186744/NCT01276639/NCT01309737/NCT01163253. People who have psoriatic arthritis or psoriasis may have more heart-related problems and cancer if they have a higher risk of cardiovascular disease: A study in people with psoriatic arthritis or psoriasis receiving tofacitinib Why was this study done? • People with psoriatic arthritis (PsA) and psoriasis (PsO) are more likely than the general population to have a disease affecting the heart and blood vessels [cardiovascular (CV) disease].• People who are more likely to have CV disease may also be more likely to have certain types of cancer.• Tofacitinib is a medicine to treat people with PsA and has been tested in people with PsO.• We wanted to know if the risk of CV disease affects the number of heart-related problems (including heart attack, stroke, or death) and cancer in people with PsA and PsO. What did the researchers do? • We used results from 10 clinical trials.• In these trials, people with PsA and PsO were taking tofacitinib 5 or 10 mg twice a day.• After the trials had ended, we measured people's risk of CV disease using a risk calculator. This risk calculator showed if they had a low, borderline, intermediate, or high risk of CV disease over the next 10 years. We also checked if they had had CV disease before treatment.• We checked if people had a group of conditions linked to CV disease: diabetes, high blood pressure, and obesity.• We counted the cases of heart-related problems and cancer in people once they started taking tofacitinib. What did the researchers find? In people with PsA and PsO taking tofacitinib:• There were more cases of heart-related problems and cancer in people who had intermediate or high risk of CV disease.• There were more cases of heart-related problems in people who had had CV disease before.• More people with diabetes, high blood pressure, and obesity had heart-related problems and cancer than people without those conditions. What do the findings mean? • It is important to measure risk and assess history of CV disease in people with PsA and PsO, including those taking tofacitinib.• We should test for cancer in people with high risk of CV disease.

In search of a 'safety zone' for glycaemic control: association between glycosylated haemoglobin levels and outcomes in patients with type 2 diabetes and cardiovascular disease.

Sodium-glucose co-transporter 2 inhibitors: strength of evidence for a cardio-renal-metabolic therapy.

Background: Accumulating evidence has demonstrated the positive effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors in managing patients with type 2 diabetes mellitus (T2DM). SGLT2 inhibitors protect patients with T2DM from cardiovascular complications and are generally safe. Aim: The aim of this study is to assess the cardiovascular effects of SGLT2 inhibitors in patients with T2DM. Methods: A systematic review was conducted using published English literature in PubMed and Google Scholar databases. Results: Most of the studies showed significant positive cardiovascular effects of SGLT2 inhibitors in patients with and without established cardiovascular disease (CVD). Empagliflozin reduced the risk of cardiovascular death, hospitalization for heart failure (HHF), cardiovascular death or heart failure, and major adverse cardiovascular events (MACE) such as nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death regardless of the number of cardiovascular risk factors. The effects of empagliflozin on cardiovascular events and mortality in patients with coronary artery bypass graft (CABG) were assessed. Further, the efficacy of empagliflozin in three different phenotypic groups, namely, younger patients with shorter duration of T2DM and highest glomerular filtration rate, women without coronary artery disease, and older adults with advanced coronary artery disease plus several comorbidities, was also assessed. The effects of canagliflozin were evaluated in patients with and without a history of CVD and with different body weights, and in those with and without prior heart failure. Treatment with canagliflozin based on multivariable-predicted cardiovascular risk factors prevented heart failure events more than treatment based on glycated hemoglobin and albuminuria alone. The efficacy of dapagliflozin was evaluated in patients with or at risk of atherosclerotic cardiovascular disease (ASCVD), heart failure status, and left ventricular ejection fraction (LVEF), as well as the elderly population. A reduction in HHF or cardiovascular death and insignificant reduction in MACE were noted. Furthermore, significant reduction in the risk of cardiovascular death and all-cause mortality in patients with heart failure with reduced ejection fraction (HFrEF) was also observed. Sotagliflozin was studied for its cardiovascular outcomes in patients with chronic kidney disease with or without albuminuria and resulted in a reduction in cardiovascular-related deaths and HHF. Conclusion: SGLT2 inhibitors have beneficial cardiovascular effects in patients with T2DM and should be incorporated into their management.

Background and aimsGlucose lowering agents that reduce the risk of major adverse cardiovascular events (MACE) would be considered a major advance. The reduction of cardiovascular risk by sodium-glucose cotransporter 2 inhibitors (SGLT-2i) has been confirmed by some large-scale randomized controlled studies (RCTs) and systematic reviews of RCTs, but exact indicators of cardiovascular risk remained controversial. Whether consistent results can be obtained in clinical practice is unclear. Therefore, in this meta-analysis, we analyzed the real-world effect of SGLT-2i on cardiovascular outcome in patients with type 2 diabetes mellitus (T2DM).MethodsWe did a real-world systematic review and meta-analysis of cardiovascular outcome of SGLT-2i in patients with T2DM. We searched PubMed and Embase for trials published up to October 23, 2019. Data search and extraction were completed with a standardized data form and any discrepancies were resolved by consensus. The primary outcome was MACE and all-cause mortality (ACM). Secondary outcomes were hospitalization for heart failure (HHF), atrial fibrillation (AF), myocardial infarction (MI), stroke, cardiovascular mortality (CVM), unstable angina (UA), heart failure (HF). Odds ratio (OR) with 95% CIs were pooled across trials, and cardiovascular outcomes were stratified by baseline incidence of cardiovascular disease (CVD), usage rate of cardiovascular benefit drug, follow-up period and region.ResultsFourteen trials enrolling 3,157,259 patients were included. SGLT-2i reduced MACE (OR, 0.71; 95% CI 0.67,0.75, P<0.001) and ACM (OR, 0.53; 95% CI 0.49,0.57, P<0.001) compared to other glucose lowering drugs (oGLD). Compared with oGLD, SGLT-2i had significantly lowered the risk of HHF (OR, 0.56; 95% CI 0.46,0.68, P<0.001), MI (OR, 0.77; 95% CI 0.73,0.81, P<0.001), stroke (OR, 0.75; 95% CI 0.72,0.78, P<0.001), CVM (OR, 0.58; 95% CI 0.49,0.69, P<0.001) and HF (OR, 0.56; 95% CI 0.48,0.67, P<0.001), but there was no benefit from UA or AF. SGLT-2i significantly reduced the risk of severe hypoglycemia (OR, 0.78; 95% CI 0.69,0.90, P<0.001) and lower limb amputation (OR, 0.83; 95% CI 0.71,0.98, P<0.001), but it may increase the risk of diabetic ketoacidosis. Subgroup analysis showed SGLT-2i reduced the risk of MACE, ACM, HHF, MI, stroke, CVM and HF with a similar benefit regardless of the incidence of CVD was (20–30)% or < 15%, (15–30)% or <15% have been treated with GLP-1 receptor agonists (GLP-1RA), >80% or <70% have been treated with statins or both GLP-1RA and statins. SGLT-2i reduced the risk of ACM in low-risk population (P<0.001). No inconsistencies were found when stratification was performed at 1 or (3–4) years of follow-up except for BKA followed up for 1 year. SGLT-2i showed similar cardiovascular benefits in the Nordic countries, Asia and the United States.ConclusionsThe predominant impact of SGLT-2i is on cardiovascular outcome driven predominantly by reduction in MACE, ACM, HHF, MI, stroke, CVM, HF, but not UA or AF. SGLT-2i has robust benefits on reducing MACE, ACM, HHF, MI, stroke, CVM and HF regardless of a history of usage rate of GLP-1RA and/or statins and /or metformin. SGLT-2i does not increase the risk of severe hypoglycemia and lower limb amputation.

Cardiovascular disease mortality rates, which had steadily declined over decades, are now plateauing or reversing due to the global rise in type 2 diabetes mellitus (T2DM) and obesity. These cardiometabolic conditions contribute significantly to atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and chronic kidney disease. Among emerging pharmacological treatments, glucagon-like peptide-1 receptor agonists, particularly semaglutide, have shown benefits beyond diabetes and obesity management, including cardioprotective and renoprotective effects. This state-of-the-art review comprehensively analyzes current evidence from clinical trials, identifies critical insights, and outlines research directions regarding semaglutide use in HF, ASCVD, and diabetic nephropathy.In ASCVD, semaglutide has demonstrated significant reductions in major adverse cardiovascular events, supported by findings from meta-analyses of trials in patients with T2DM and the SELECT trial for patients without T2DM. In a prespecified analysis of the SELECT trial, semaglutide demonstrated significant reductions in cardiovascular mortality and HF hospitalizations for patients with HF and ASCVD. In HF with preserved ejection fraction and mildly reduced ejection fraction, semaglutide improved symptoms, physical function, natriuretic peptide levels, echocardiographic parameters, and HF hospitalizations, as shown in the STEP-HFpEF program and a pooled analysis of trials. Furthermore, evidence from the FLOW trial underscores semaglutide's renal and cardiovascular benefits in diabetic nephropathy, irrespective of body mass index. While these findings suggest semaglutide's efficacy in cardiorenal diseases, gaps in evidence remain, including the need for event-driven trials in HF populations without ASCVD and irrespective of obesity. Future research should address these gaps, which could potentially update guideline recommendations.

The global epidemic of type 2 diabetes mellitus (T2DM) has substantial implications for cardiovascular disease–related morbidity and mortality.1 The prevalence of T2DM in patients with heart failure (HF) is high, with strong and independent association between T2DM and incident HF observed in multiple prospective studies and in randomized-controlled clinical trials. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which enrolled subject’s ≥55 years of age with hypertension and ≥1 risk factor, patients with T2DM had a 2-fold risk for HF hospitalization or death after adjustment for other risk factors (RR, 1.95). The association with T2DM was independent of coronary artery disease and at least equivalent in magnitude and greater than that for electrocardiographic left ventricular (LV) hypertrophy.2 All measures of glycemia including fasting, postprandial, measures of insulin resistance, and hemoglobin A1c (HbA1c) have been associated with risk of developing HF, with the association extending to both HF with preserved ejection fraction and to HF with reduced ejection fraction.3,4 A substantial body of evidence from preclinical studies, endomyocardial biopsies in humans and more recently with cardiac MRI, support increased myocardial stiffness in T2DM related to alteration in extracellular matrix. There are multiple proximate mediators that have been hypothesized to play a role including advanced glycation end product deposition and reactive oxygen species that may increase myocardial stiffness during diastole, by cross-linking collagen or by enhancing collagen formation.5,6 Another pernicious proximal mediator is the elevation in postprandial lipids, such as remnant lipoproteins, characteristic of atherogenic dyslipidemia, a highly prevalent abnormality in T2DM, that may result in direct myocellular deposition of lipid, leading to microcirculatory dysfunction, alteration in substrate use and mitochondrial dysfunction.7,8 Indeed, positron emission tomography studies show reduced myocardial glucose uptake in favor of fatty acid …

Background: Hypertension (HTN), a prevalent comorbidity in type 2 diabetes mellitus (T2DM), increases the risk of cardiovascular (CV) events, mortality, and kidney complications. However, optimal blood pressure (BP) targets in patients with T2DM remain unclear. Research Question: Does intensive BP control, compared to standard targets, reduce CV, renal, and mortality outcomes in patients with T2DM? Aims: We aim to conduct an updated meta-analysis to evaluate the effects of intensive vs. standard BP control on CV and kidney outcomes and mortality in T2DM patients. Methods: A comprehensive search of PubMed, Cochrane Library, and Scopus was conducted through December 2024 for trials comparing intensive vs. standard BP control in patients with T2DM. Outcomes assessed included all-cause mortality, CV mortality, major adverse CV events (MACE), stroke, myocardial infarction (MI), incident heart failure (HF), chronic kidney disease (CKD) development, albuminuria, and serious adverse events (SAEs). Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using a random effects model. Results: 28 trials encompassing 104,634 patients were included. Intensive BP control significantly reduced the risk of CV mortality (RR: 0.75, 95% CI: 0.65–0.87, P = 0.0001), all-cause mortality (RR: 0.85, 95% CI: 0.76–0.95, P = 0.004), MACE (RR: 0.81, 95% CI: 0.75–0.87, P &lt; 0.00001), stroke (RR: 0.70, 95% CI: 0.61–0.80, P &lt; 0.00001), MI (RR: 0.86, 95% CI: 0.79–0.94, P = 0.001), HF (RR: 0.78, 95% CI: 0.64–0.96, P = 0.02), and albuminuria (RR: 0.89, 95% CI: 0.82–0.97, P = 0.005). There were no significant differences in CKD development (RR: 1.08, 95% CI: 0.92–1.26, P = 0.36) or SAEs (RR: 1.16, 95% CI: 0.97–1.40, P = 0.10). Conclusions: Intensive BP control in patients with T2DM was associated with a lower risk of all-cause mortality, CV mortality, MACE, stroke, MI, HF, and albuminuria as compared to standard control, without an increased risk of serious adverse events.

Background: In the 2018 AHA/ACC Cholesterol guideline, risk stratification is an essential element. The use of a Pooled Cohort Equation (PCE) is recommended for individuals without atherosclerotic cardiovascular disease (ASCVD), and the new dichotomous classification of very high-risk vs. high-risk has been introduced for patients with ASCVD. These distinct risk stratification systems mainly rely on traditional risk factors, raising the possibility that a single model can predict major adverse cardiovascular events (MACEs) in persons with and without ASCVD. Methods: We studied 11,335 ARIC participants with (n=885) and without (n=10,450) a history of ASCVD (myocardial infarction, ischemic stroke, and symptomatic peripheral artery disease) at baseline (1996-98). We modeled factors in the PCE and the new classification for ASCVD patients (Figure legend) in a single CVD prediction model. We examined their associations with MACEs (myocardial infarction, stroke, and heart failure) using Cox models and evaluated the discrimination and calibration for a single model including those factors. Results: During a median follow-up of 18.4 years, there were 3,658 MACEs (3,105 in participants without ASCVD). In general, the factors in the PCE and the risk classification system for ASCVD patients were associated similarly with MACEs regardless of baseline ASCVD status, although age and systolic blood pressure showed significant interactions. A single model with these predictors and the relevant interaction terms showed good calibration and discrimination for those with and without ASCVD (c-statistic=0.729 and 0.704, respectively) (Figure). Conclusion: A single CVD prediction model performed well in persons with and without ASCVD. This approach will provide a specific predicted risk to ASCVD patients (instead of dichotomy of very high vs. high risk) and eliminate a practice gap between primary vs. secondary prevention due to different risk prediction tools.

Introduction: Lipoprotein(a) [Lp(a)] is associated with increased atherosclerotic cardiovascular disease (ASCVD) events. However, whether the optimal Lp(a) threshold for risk-assessment should differ based on baseline ASCVD status is unknown. Hypothesis: To assess the association between Lp(a) and major adverse cardiovascular events (MACE) among patients with and without a history of ASCVD. Methods: Retrospective cohort of patients with Lp(a) measured at two academic medical centers in Boston, MA from 2000-2019. To assess the association of Lp(a) with incident MACE (cardiovascular mortality, myocardial infarction, or ischemic stroke), the following Lp(a) percentile groups were generated: 1 st -50 th (0 - 41 nmol/L; reference), 51 st -70 th (42 - 111 nmol/L), 71 st -90 th (112 - 215 nmol/L), 91 st -100 th (&gt;216 nmol/L). Individuals with severe renal dysfunction or a malignant neoplasm were excluded. Cox proportional hazards modeling was used to assess the association of Lp(a) percentile group with MACE. Results: After applying eligibility criteria, 16,419 patients (median age 60, 41% female) were analyzed with a median follow up of 11.9 years. Patients with ASCVD were older and had higher rates of cardiovascular risk factors. Among the 10,181 (62%) patients with a history of ASCVD, individuals in the 71 st -90 th and 91 st -100 th percentile groups had similarly increased hazards of MACE (adjusted HR = 1.33, p&lt;0.001 and adjusted HR = 1.34, p&lt;0.001 respectively). Among the 6,238 individuals without baseline ASCVD, only individuals in the 91 st -100 th Lp(a) percentile group had a significantly increase hazard of MACE (adjusted HR 2.05, p&lt;0.001), Figure . Conclusions: In a large, contemporary US cohort, elevated Lp(a) is independently associated with long-term MACE among individuals with and without baseline ASCVD. Our results suggest that the Lp(a) threshold for risk assessment may be lower in secondary prevention when compared with primary prevention.

Cardiovascular Protection in People With Diabetes.

Background: We evaluated the incremental contribution of chronic kidney disease (CKD) to the risk of major adverse cardiovascular (CV) events (MACE), heart failure (HF), and all-cause mortality (ACM) in type 2 diabetes mellitus (T2DM) patients and its importance relative to the presence of other cardio-renal-metabolic (CaReMe) comorbidities. Methods: Patients (≥40 years) were identified at the time of T2DM diagnosis from US (Humedica/Optum) and UK (Clinical Practice Research Datalink) databases. Patients were monitored post-diagnosis for modified MACE (myocardial infarction, stroke, ACM), HF, and ACM. Adjusted hazard ratios were obtained using Cox proportional-hazards regression to evaluate the relative risk of modified MACE, HF, and ACM due to CKD. Patients were stratified by the presence or absence of atherosclerotic CV disease (ASCVD) and age. Results: Between 2011 and 2015, of 227,224 patients identified with incident T2DM, 40,063 (17.64%) had CKD. Regardless of prior ASCVD, CKD was associated with higher risk of modified MACE, HF, and ACM; this excess hazard was more pronounced in older patients with prior ASCVD. In time-to-event analyses in the overall cohort, patients with T2DM + CKD or T2DM + CKD + hypertension + hyperlipidemia had increased risks for modified MACE, HF, and ACM versus patients with T2DM and no CaReMe comorbidities. Patients with CKD had higher risks for and shorter times to modified MACE, HF, and ACM than those without CKD. Conclusion: In T2DM patients, CKD presence was associated with higher risk of modified MACE, HF, and ACM. This may have risk-stratification implications for T2DM patients based on background CKD and highlights the potential importance of novel renoprotective strategies.

Sodium-glucose co-transporter 2 inhibitors for heart failure: clinical trial efficacy and clinical practice effectiveness.

ObjectivesEvaluate risk of major adverse cardiovascular events (MACE) with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA) with or without a history of atherosclerotic cardiovascular...

<h3>Objectives</h3> Evaluate risk of major adverse cardiovascular events (MACE) with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA) with or without a history of atherosclerotic...