The Landscape of Glucose-Lowering Therapy and Cardiovascular Outcomes: From Barren Land to Metropolis.
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ABSTRACT:
SUBMITTER: Nasrallah MP
PROVIDER: S-EPMC5705897 | biostudies-other | 2017
REPOSITORIES: biostudies-other
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The Landscape of Glucose-Lowering Therapy and Cardiovascular Outcomes: From Barren Land to Metropolis.
Nasrallah Mona P MP Abi Khalil Charbel C Refaat Marwan M MM
BioMed research international 20171114
The choice of glucose-lowering therapy (GLT) has expanded to include 11 different classes in addition to insulin. Since the 2008 Food and Drug Administration guidance for industry and mandate of demonstrating cardiovascular (CV) safety prior to any new drug approval, there were several trials primarily conducted to establish that goal. Some had neutral effects, while there were positively beneficial outcomes with more recent studies. Hospitalization for congestive heart failure has also been a h ...[more]
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Project description:BackgroundIntensive glucose lowering has previously been shown to increase mortality among persons with advanced type 2 diabetes and a high risk of cardiovascular disease. This report describes the 5-year outcomes of a mean of 3.7 years of intensive glucose lowering on mortality and key cardiovascular events.MethodsWe randomly assigned participants with type 2 diabetes and cardiovascular disease or additional cardiovascular risk factors to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level of 7 to 7.9%). After termination of the intensive therapy, due to higher mortality in the intensive-therapy group, the target glycated hemoglobin level was 7 to 7.9% for all participants, who were followed until the planned end of the trial.ResultsBefore the intensive therapy was terminated, the intensive-therapy group did not differ significantly from the standard-therapy group in the rate of the primary outcome (a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) (P=0.13) but had more deaths from any cause (primarily cardiovascular) (hazard ratio, 1.21; 95% confidence interval [CI], 1.02 to 1.44) and fewer nonfatal myocardial infarctions (hazard ratio, 0.79; 95% CI, 0.66 to 0.95). These trends persisted during the entire follow-up period (hazard ratio for death, 1.19; 95% CI, 1.03 to 1.38; and hazard ratio for nonfatal myocardial infarction, 0.82; 95% CI, 0.70 to 0.96). After the intensive intervention was terminated, the median glycated hemoglobin level in the intensive-therapy group rose from 6.4% to 7.2%, and the use of glucose-lowering medications and rates of severe hypoglycemia and other adverse events were similar in the two groups.ConclusionsAs compared with standard therapy, the use of intensive therapy for 3.7 years to target a glycated hemoglobin level below 6% reduced 5-year nonfatal myocardial infarctions but increased 5-year mortality. Such a strategy cannot be recommended for high-risk patients with advanced type 2 diabetes. (Funded by the National Heart, Lung and Blood Institute; ClinicalTrials.gov number, NCT00000620.).
| S-EPMC4083508 | biostudies-literature
Project description:The effects on cardiovascular disease (CVD) by treatment recommendations on prevention of atherosclerotic CVD remain to be evaluated. The objectives were to assess treatment gap for low density lipoprotein cholesterol (LDL-C) according to guidelines, potential impact on CVD outcomes, and possible avoided economic costs, in post myocardial infarction (MI) patients, if target LDL-C levels of ≤1.8 mmol/L would be achieved.All patients registered in the Swedish Secondary Prevention after Heart Intensive care Admission register, with one-year post-MI follow-up during 2013 were selected. The REACH risk prediction and a calibrated model for recurrent cardiovascular events and death were used to estimate unadjusted risk prediction based on the REACH equation henceforth called base case, and calibrated CVD outcomes based on gender-specific risk factors. The predicted impact of the LDL-C reduction on the risk of CVD was based on the Cholesterol Treatment Trialists´ Collaboration findings.A sample of n = 5904 patients (74% men) with a mean age of 64 years were included. Around 70% did not reach LDL-C target ≤1.8 mmol/L. Over a 10-year period, 820-2262 events were predicted to occur in those who did not reach target corresponding to 20% - 55% risk of CVD events. To achieve LDL-C target, the mean LDL-C had to be reduced by 0.73 mmol/L (29%). If this LDL-C reduction was achieved, 195-544 life years, 132-343 CVD events, and 7.9-20.9 million Swedish crowns (MSEK) of direct costs, and 19.3-51.0 MSEK of total costs would be avoided.Lowering of LDL cholesterol to achieve target levels according to guidelines for post-MI patients may lead to fewer cardiovascular events and avoidance of event costs.
| S-EPMC5559790 | biostudies-other
Project description:AimsTECOS was a randomized, double-blind, placebo-controlled trial assessing the impact of sitagliptin vs. placebo on cardiovascular outcomes when added to usual care in patients with type 2 diabetes. We report the use of concomitant diabetes medications and the risk for progression to insulin during follow-up.Materials and methodsTECOS enrolled 14 671 participants with HbA1c 6.5%-8.0% on monotherapy with metformin, pioglitazone, sulfonylurea (SU), or dual therapy with two oral agents or insulin with or without metformin. Subsequent diabetes management was by the participant's usual care physician. Time to initiation of insulin and risk of hypoglycaemia were estimated using Cox proportional hazards models.ResultsThe most common glucose-lowering regimens at baseline were metformin monotherapy (30.2%), SU monotherapy (8.5%), metformin/SU therapy (35.1%), and insulin with or without metformin (13.9% and 8.6%, respectively). Over a median 3.0 years' follow-up, diabetes therapy was intensified in 25.2% of participants (sitagliptin 22.0%, placebo 28.3%). Medications most commonly added were SU (8.3%) or insulin (8.8%). Insulin initiation in the usual care setting occurred at mean (standard deviation) HbA1c of 8.5 (1.5)%. Sitagliptin did not impact rates of severe hypoglycaemia, but delayed progression to insulin when added to metformin or metformin/SU regimens.ConclusionConsistent with the trial's pragmatic design, TECOS participants underwent typical progression of diabetes medications. Sitagliptin was associated with lower HbA1c, without increased risk for severe hypoglycaemia and was associated with delayed progression to insulin when added to metformin with or without SU.
| S-EPMC6354756 | biostudies-literature
Project description:Background and objectivesSeveral clinical practice guidelines noted the potential benefits of urate-lowering therapy on cardiovascular disease and CKD progression; however, the effect of this regimen remains uncertain. In this systematic review, we aimed to evaluate the efficacy of urate-lowering therapy on major adverse cardiovascular events, all-cause mortality, kidney failure events, BP, and GFR.Design, setting, participants, & measurementsWe systematically searched MEDLINE, Embase, and the Cochrane databases for trials published through July 2020. We included prospective, randomized, controlled trials assessing the effects of urate-lowering therapy for at least 6 months on cardiovascular or kidney outcomes. Relevant information was extracted into a spreadsheet by two authors independently. Treatment effects were summarized using random effects meta-analysis.ResultsWe identified 28 trials including a total of 6458 participants with 506 major adverse cardiovascular events and 266 kidney failure events. Overall urate-lowering therapy did not show benefits on major adverse cardiovascular events (risk ratio, 0.93; 95% confidence interval, 0.74 to 1.18) and all-cause mortality (risk ratio, 1.04; 95% confidence interval, 0.78 to 1.39) or kidney failure (risk ratio, 0.97; 95% confidence interval, 0.61 to 1.54). Nevertheless, urate-lowering therapy attenuated the decline in the slope of GFR (weighted mean difference, 1.18 ml/min per 1.73 m2 per year; 95% confidence interval, 0.44 to 1.91) and lowered the mean BP (systolic BP: weighted mean difference, -3.45 mm Hg; 95% confidence interval, -6.10 to -0.80; diastolic BP: weighted mean difference, -2.02 mm Hg; 95% confidence interval, -3.25 to -0.78). There was no significant difference (risk ratio, 1.01; 95% confidence interval, 0.94 to 1.08) in the risk of adverse events between the participants receiving urate-lowering therapy and the control group.ConclusionsUrate-lowering therapy did not produce benefits on the clinical outcomes, including major adverse cardiovascular events, all-cause mortality, and kidney failure. Thus, there is insufficient evidence to support urate lowering in patients to improve kidney and cardiovascular outcomes.
| S-EPMC7646244 | biostudies-literature
Project description:BackgroundRandomized, controlled cardiovascular outcome trials may not be fully representative of the management of patients with type 2 diabetes across different geographic regions. We conducted analyses of data from the multinational CVD-REAL consortium to determine the association between initiation of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and cardiovascular outcomes, including subgroup analyses based on patient characteristics.MethodsDe-identified health records from 13 countries across three continents were used to identify patients newly-initiated on SGLT-2i or other glucose-lowering drugs (oGLDs). Propensity scores for SGLT-2i initiation were developed in each country, with 1:1 matching for oGLD initiation. In the matched groups hazard ratios (HRs) for hospitalization for heart failure (HHF), all-cause death (ACD), the composite of HHF or ACD, myocardial infarction (MI) and stroke were estimated by country, and pooled using a weighted meta-analysis. Multiple subgroup analyses were conducted across patient demographic and clinical characteristics to examine any heterogeneity in treatment effects.ResultsFollowing matching, 440,599 new users of SGLT-2i and oGLDs were included in each group. Mean follow-up time was 396 days for SGLT-2i initiation and 406 days for oGLDs initiation. SGLT-2i initiation was associated with a lower risk of HHF (HR: 0.66, 95%CI 0.58-0.75; p < 0.001), ACD (HR: 0.52, 95%CI 0.45-0.60; p < 0.001), the composite of HHF or ACD (HR: 0.60, 95%CI 0.53-0.68; p < 0.001), MI (HR: 0.85, 95%CI 0.78-0.92; p < 0.001), and stroke (HR: 0.78, 95%CI 0.72-0.85; p < 0.001); regardless of patient characteristics, including established cardiovascular disease, or geographic region.ConclusionsThis CVD-REAL study extends the findings from the SGLT-2i clinical trials to the broader setting of an ethnically and geographically diverse population, and across multiple subgroups. Trial registration NCT02993614.
| S-EPMC8325810 | biostudies-literature
Project description:This study investigated the hypothesis that baseline calcified coronary atherosclerosis may determine cardiovascular disease events in response to intensive glycemic control within the Veterans Affairs Diabetes Trial (VADT).At baseline, 301 type 2 diabetic participants in the VADT, a randomized trial comparing the effects of intensive versus standard glucose lowering on cardiovascular events, had baseline coronary atherosclerosis assessed by coronary artery calcium (CAC) measured by computed tomography. Participants were followed over the 7.5-year study for development of cardiovascular end points.During a median follow-up duration of 5.2 years, 89 cardiovascular events occurred. Although intensive glucose-lowering therapy did not significantly reduce cardiovascular events in the substudy cohort as a whole, there was evidence that the response was modified by baseline CAC, as indicated by significant P values for treatment by log(CAC + 1) interaction terms in unadjusted and multivariable-adjusted models (0.01 and 0.03, respectively). Multivariable-adjusted hazard ratios (HRs) for the effect of treatment indicated a progressive diminution of benefit with increasing CAC. Subgroup analyses were also conducted for clinically relevant CAC categories: those above and below an Agatston score of 100. Among those randomized to intensive treatment, for the subgroup with CAC >100, 11 of 62 individuals had events, while only 1 of 52 individuals with CAC < or = 100 had an event. The multivariable HR for intensive treatment for those with CAC >100 was 0.74 (95% CI 0.46-1.20; P = 0.21), while for the subgroup with CAC < or = 100, the corresponding HR was 0.08 (0.008-0.77; P = 0.03), with event rates of 39 and 4 per 1,000 person-years, respectively.These data indicate that intensive glucose lowering reduces cardiovascular events in those with less extensive calcified coronary atherosclerosis.
| S-EPMC2768182 | biostudies-literature
Project description:INTRODUCTION:Among the most pressing clinical decisions in type 2 diabetes treatments are which drugs should be used after metformin is no longer sufficient, and whether sulfonylureas (SUs) should remain as a suitable second-line treatment. In this article we summarize current evidence on the long-term safety risks associated with SU therapy relative to other oral glucose-lowering therapies. METHODS:The MEDLINE database and Clinicaltrials.gov were searched for observational and experimental studies comparing the safety of SUs to that of other diabetes medications in people with type 2 diabetes mellitus through December 15, 2015. Studies with at least 1 year of follow-up, which explicitly examined major cardiovascular events or death in patients who showed no evidence of serious conditions at baseline, were selected for inclusion in meta-analyses. RESULTS:SU treatment was associated with an elevated risk relative to treatment with metformin (METF), thiazolidinedione (TZD), dipeptidyl peptidase-4 inhibitor (DPP-4), and glucagon-like peptide-1 (GLP-1) agonist classes, either when compared alone (as a monotherapy) or when used in combination with METF. Significant findings were almost entirely derived from nontrial data and not confirmed by smaller, efficacy designed randomized controlled trials whose effects were in the same direction but much more imprecise. CONCLUSION:Although much of the evidence is derived and will continue to come from observational studies, the methodological rigor of such studies is questionable. A key challenge for evaluators is the extent to which they should incorporate evidence from study designs that are quasi-experimental.
| S-EPMC6064594 | biostudies-literature
Project description:BackgroundLipid-lowering therapy (LLT) is one of the key strategies for reducing the atherosclerotic cardiovascular disease (ASCVD) burden. However, little is known about the percentage of people in need of different LLT regimens to achieve optimal targets of low-density lipoprotein cholesterol (LDL-C), and the corresponding cost and benefit.MethodsWe conducted a simulation study based on the data from the nationwide China PEACE MPP population cohort (2015-2020), from which we included 2,904,914 participants aged 35-75 years from all the 31 provinces in mainland China. Participants were grouped based on their 10-year ASCVD risks, then entered into a Monte Carlo model which was used to perform LLT intensification simulation scenarios to achieve corresponding LDL-C goals in each risk stratification.ResultsAfter standardizing age and sex, the proportions of participants included at low, moderate, high, and very-high risk were 70.8%, 15.6%, 11.5%, and 2.1%, respectively. People who failed to achieve the corresponding LDL-C goals -8.1% at low risk, 19.6% at moderate risk, 53.2% at high risk, and 93.6% at very-high risk (either not achieving the goal or not receiving LLT)-would be in need of the LLT intensification simulation. After the use of atorvastatin 20 mg was simulated, over 99% of the population at low or moderate risk could achieve the LDL-C goals; while 11.3% at high and 24.5% at very-high risk would still require additional non-statin therapy. After the additional use of ezetimibe, there were still 4.8% at high risk and 11.3% at very-high risk in need of evolocumab; and 99% of these two groups could achieve the LDL-C goals after the use of evolocumab. Such LLT intensification with statin, ezetimibe, and evolocumab would annually cost $2.4 billion, $4.2 billion, and $24.5 billion, respectively, and prevent 264,170, 18,390, and 17,045 cardiovascular events, respectively.ConclusionsModerate-intensity statin therapy is pivotal for the attainment of optimal LDL-C goals in China, and around 10-25% of high- or very-high-risk patients would require additional non-statin agents. There is an opportunity to reduce the rising ASCVD burden in China by optimizing LLT.
| S-EPMC8996051 | biostudies-literature
Project description:Type 2 Diabetes Mellitus (T2DM) is associated with a high risk of atherosclerotic cardiovascular (CV) disease. Among the well-known pathophysiologic factors, crucial roles are played by endothelial dysfunction (caused by oxidative stress and inflammation hyperglycemia-linked), increased activity of nuclear factor kB, altered macrophage polarization, and reduced synthesis of resident endothelial progenitor cells. As consequence, a potentially rapid progression of the atherosclerotic disease with a higher propensity to unstable plaque is arguable, finally leading to significantly increased cardiovascular mortality. Main managements are focused on both prevention and early diagnosis, by targeted treatment of hyperglycemia and vascular complications. Innovative therapeutic approaches for T2DM seek to customize the antidiabetic treatment to each patient in order to optimize glucose-lowering effects, minimize hypoglycemia and adverse effects, and prevent cardiovascular events. The newer drugs (e.g., Glucagon Like Peptide-1 Receptor Agonists, GLP-1 RAs; Sodium GLucose coTransporter-2 inhibitors, SGLT2is; DiPeptidyl Peptidase-4 inhibitors, and DPP4is) impact body weight, lipid parameters, and blood pressure, as well as endothelial (dys)functions, inflammatory markers, biomarkers of both oxidative stress, and subclinical atherosclerosis. The present review summarizes the results of the main trials focused on the cardiovascular safety of these drugs from the CV standpoint.
| S-EPMC7230245 | biostudies-literature
Project description:ObjectiveTo determine whether the benefits of dapagliflozin in patients with heart failure and reduced ejection fraction (HFrEF) and type 2 diabetes in the Dapagliflozin And Prevention of Adverse-Outcomes in Heart Failure trial (DAPA-HF) varied by background glucose-lowering therapy (GLT).Research design and methodsWe examined the effect of study treatment by the use or not of GLT and by GLT classes and combinations. The primary outcome was a composite of worsening heart failure (hospitalization or urgent visit requiring intravenous therapy) or cardiovascular death.ResultsIn the 2,139 type 2 diabetes patients, the effect of dapagliflozin on the primary outcome was consistent by GLT use or no use (hazard ratio 0.72 [95% CI 0.58-0.88] vs. 0.86 [0.60-1.23]; interaction P = 0.39) and across GLT classes.ConclusionsIn DAPA-HF, dapagliflozin improved outcomes irrespective of use or no use of GLT or by GLT type used in patients with type 2 diabetes and HFrEF.
| S-EPMC7809714 | biostudies-literature