Predictors of heart failure development in type 2 diabetes: a practical approach.
ABSTRACT: PURPOSE OF REVIEW:Although type 2 diabetes (T2D) is one of the most important risk factors that leads to the development of de novo heart failure, there are limited data, particularly from a practical/qualitative standpoint, about predictors of heart failure in this population. RECENT FINDINGS:Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been shown to prevent the development of heart failure and the composite of heart failure and cardiovascular death in patients with T2D without known heart failure who have either established atherosclerotic vascular disease or multiple risk factors. The concept of primary prevention of heart failure has led many clinicians to inquire if there are specific risk/enrichment factors that may predict an increased risk of heart failure. SUMMARY:In this review, we identify some general and diabetes-specific risk factors that are associated with an increased risk of developing heart failure in people with T2D.
Project description:Type 2 diabetes (T2D) is associated with an increased risk of macro- and microvascular complications, including cardiovascular disease (CVD), heart failure (HF), and chronic kidney disease (CKD). Of the currently available glucose-lowering therapies, sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are the only class to target the pathophysiologic increase in renal glucose reabsorption in patients with T2D. In CV outcomes trials of SGLT-2is in patients with T2D and established CVD or varying levels of CV risk, empagliflozin, canagliflozin, and dapagliflozin were associated with significant improvements in the risk of composite CV and renal outcomes compared with placebo that extended beyond their glycemic effects. Real-world observational studies have also reported improvements in CV outcomes with SGLT-2is compared with other glucose-lowering therapy in routine clinical practice. This review describes the pleiotropic effects of SGLT-2is and discusses the potential mechanisms for these effects as well as how they potentially provide benefits beyond glycemic control in patients with T2D. These favorable nonglycemic effects indicate that SGLT-2is may be of particular benefit in patients with diabetic complications, such as CVD, HF, or CKD. Ongoing large randomized trials in specific patient populations, including those with CVD, HF, or CKD (with or without T2D), may help to confirm the benefits of SGLT-2is in these patients and further elucidate the potential mechanisms of their pleiotropic effects. FUNDING: AstraZeneca.
Project description:<h4>Aim</h4>To evaluate the impact of sodium glucose cotransporter 2 inhibitors (SGLT-2i) on risk of heart failure hospitalization in patients with type 2 diabetes.<h4>Methods</h4>We searched the PubMed, Embase, The Cochrane Library, CNKI, Wanfang, CBM, and other web knowledge databases for data from randomized controlled trials. We performed statistical analyses by using review Manager (RevMan) 5.3 and STATA 12.0 for meta-analysis.<h4>Results</h4>Eight randomized controlled trials that compared SGLT-2i <i>versus</i> placebo met our inclusion criteria and were included in the study. The final meta-analysis included a total of 55,763 type 2 diabetes patients. Compared with placebo, SGLT-2i reduced the risk of heart failure hospitalization (RR, 0.63; 95% CI, 0.53 to 0.74; <i>P</i> < 0.00001), MACE (defined as cardiovascular death, myocardial infarction, or ischemic stroke) (RR, 0.92; 95% CI, 0.86 to 0.98; <i>P</i> < 0.007), cardiovascular death (RR, 0.78; 95%CI, 0.62 to 0.99; <i>P</i> = 0.04) in type 2 diabetes patients. SGLT-2i could reduce the risk of death from any cause (RR, 0.77; 95% CI, 0.59 to 1.01; <i>P</i> = 0.06) without statistical significance in type 2 diabetes patients.<h4>Conclusion</h4>Compared with placebo, SGLT-2i may reduce the risk of heart failure hospitalization, MACE, and cardiovascular death. Therefore, SGLT-2i may be an ideal choice for type 2 diabetes mellitus patient with heart failure. These results will help inform practitioners, patients, and authorities making appropriate choices in hypoglycemic therapy clinical practice.
Project description:Type 2 diabetes (T2D) is associated with numerous comorbidities that significantly reduce quality of life, increase mortality and complicate treatment decisions. In a recent cardiovascular outcomes trial, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME), the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin was shown to reduce cardiovascular (CV) mortality and heart failure in high-risk patients with T2D with a previous CV event or with established CV disease (CVD). Recently published data from the Canagliflozin Cardiovascular Assessment Study (CANVAS-PROGRAM) study suggested that the cardiovascular benefits of empagliflozin are also seen with the SGLT2-inhibitor canagliflozin, indicating a class effect of SGLT2 inhibitors. Evidence for a class effect has also been shown by meta-analyses and real-world studies, including the Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL) and The Health Improvement Network (THIN) databases. These findings also suggest the results of EMPA-REG OUTCOME can be applied to patients with T2D with a broader CV risk profile, including people at low risk of CVD.
Project description:INTRODUCTION:A diagnosis of type 2 diabetes (T2D) more than doubles the risk of cardiovascular disease (CVD), with heart failure (HF) being one of the most common complications with a severe prognosis. The landmark Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Paitients (EMPA-REG OUTCOME) study demonstrated that treatment with the sodium glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin rapidly and significantly reduces CVD mortality and admission rates for HF. However, the mechanisms behind this reduction in clinical events are unknown.This study was designed to investigate the effects of the SGLT-2 inhibitor empagliflozin on myocardial perfusion and function in patients with T2D and high CVD risk. METHODS AND ANALYSIS:In this investigator-initiated, randomised, double-blind controlled clinical trial, 92 patients with T2D and established CVD or high CVD risk will be randomised to treatment with empagliflozin 25?mg or a matching placebo for 13 weeks. The primary outcome measure is change in myocardial flow reserve measured quantitatively by Rubidium-82 position emission tomography. In a substudy, invasive haemodynamics at rest and during exercise will be measured at baseline and following the intervention, using right heart catheterisation. ETHICS AND DISSEMINATION:The study protocol (v7, 02/08/2018) has been approved by the Ethics Committee of the Capital Region, Danish Data Protection Board and the Danish Medicines Agency, and it will be monitored according to the Good Clinical Practice regulations from the International Conference on Harmonization. The results be submitted to international peer-reviewed journals and be presented at conferences. The data will be made available to the public via EudraCT and www.clinicaltrials.gov. TRIAL REGISTRATION NUMBER:NCT03151343.
Project description:Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are currently used as second-line therapy for treatment of patients with type 2 diabetes mellitus (T2DM). Based on the results from dedicated cardiovascular outcome trials (CVOTs), current guidelines suggest the use of SGLT-2 inhibitors for patients with T2DM and established atherosclerotic cardiovascular disease (ASCVD) or heart failure. The cardiovascular safety profile of dapagliflozin, a novel SGLT-2 inhibitor, has been recently explored in large CVOTs. Treatment with dapagliflozin reduced the risk of the composite outcome of cardiovascular mortality or hospitalization for heart failure compared with placebo, both among patients with T2DM who had or were at risk of ASCVD, as well as among patients with heart failure and a reduced ejection fraction. The observed cardiovascular benefit was mainly attributed to the lower rate of hospitalization for heart failure. Additionally, treatment with dapagliflozin was associated with a lower rate of renal adverse events. The safety and efficacy of dapagliflozin on glycemic and non-glycemic endpoints has been also well established in a series of other clinical trials and real-word studies. The aim of the present review is to summarize the available evidence regarding the cardiovascular profile of dapagliflozin in patients with T2DM. Overall, by reducing the rate of hospitalization for heart failure and ameliorating renal adverse events, dapagliflozin is a valuable option for the management of patients with T2DM and multiple cardiovascular risk factors.
Project description:Background We explored whether clinically relevant baseline characteristics of patients with type 2 diabetes can modify the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RA) or sodium-glucose cotransporter-2 inhibitors (SGLT-2i) on the risk of major adverse cardiovascular events (MACE). Methods We investigated Medline and EMBASE through June 2019. We included randomized clinical trials reporting the effect of GLP-1 RA or SGLT-2i on MACE in subgroups of patients with type 2 diabetes, identified through key baseline factors: established cardiovascular disease; heart failure; chronic kidney disease; uncontrolled diabetes; duration of diabetes; hypertension; obesity; age; gender and race. Hazard ratios (HRs) and 95% confidence intervals (CIs) from trials were meta-analyzed using random-effects models. Results Ten trials enrolling 89,790 patients were included in the analyses. Subgroup meta-analyses showed a 14% risk reduction of MACE in patients with established cardiovascular disease [GLP1-RA: HR, 0.86 (95% CI, 0.80–0.93); SGLT-2i: 0.86 (0.80–0.93)], and no effect in at-risk patients without history of cardiovascular events [GLP1-RA: 0.94 (0.82–1.07); SGLT-2i: 1.00 (0.87–1.16)]. We observed a trend toward larger treatment benefits with SGLT-2i among patients with chronic kidney disease [0.82 (0.69–0.97)], and patients with uncontrolled diabetes for both GLP1-RA or SGLT-2i [GLP1-RA: 0.82 (0.71–0.95); SGLT-2i: 0.84 (0.75–0.95)]. Uncontrolled hypertension, obesity, gender, age and race did not appear to modify the effect of these drugs. Conclusions In this exploratory analysis, history of cardiovascular disease appeared to modify the treatment effect of SGLT2i or GLP1-RA on MACE. Chronic kidney disease and uncontrolled diabetes should be further investigated as potential effect modifiers.
Project description:PURPOSE OF REVIEW:We highlight the unique properties of the sodium-glucose cotransporter-2 (SGLT-2 inhibitors) which may lend favorably to their efficient integration in the background of other heart failure (HF) therapies. We also discuss the unique aspects of SGLT-2 inhibitor dosing, lack of titration needs, effects on kidney function and electrolytes, diuretic activity, and safety in the high-risk peri-hospitalization window. RECENT FINDINGS:Dapagliflozin was recently approved for the treatment of heart failure with reduced ejection fraction (HFrEF), irrespective of the presence or absence of type 2 diabetes mellitus (T2DM) based on the findings of the pivotal DAPA-HF trial. All SGLT-2 inhibitors are once daily medications with minimal drug-drug interactions and do not require titration (for HF treatment) unlike other HF medications. SGLT-2 inhibitors offer modest weight loss and blood pressure reduction without major adverse effects of hyperkalemia, making it ideal for near-simultaneous initiation with other HF medications, and use in high-risk populations (including older adults). Moreover, SGLT-2 inhibitors appear to afford long-term kidney protection in diverse populations. SGLT-2 inhibitors are the latest class of therapies to demonstrate important clinical benefits among patients with HFrEF, and their pharmacological properties favor ease of use and integration in multi-drug disease-modifying regimens.
Project description:Diabetes mellitus in Asia accounts for more than half of the global prevalence. There is a high prevalence of cardiovascular disease (CVD) in the region among people with type 2 diabetes mellitus (T2DM) and it is often associated with multiple risk factors including hypertension, renal disease and obesity. The early onset of T2DM and the eventual long disease duration portends an increasing proportion of the population to premature CVD. In addition to lowering blood glucose, sodium-glucose co-transporter-2 (SGLT-2) inhibitors exert favourable effects on multiple risk factors (including blood pressure, body weight and renal function) and provide an opportunity to reduce the risk of CVD in patients with T2DM. In this article, we consolidated the existing literature on SGLT-2 inhibitor use in Asian patients with T2DM and established contemporary guidance for clinicians. We extensively reviewed recommendations from international and regional guidelines, published data from clinical trials in the Asian population (dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, luseogliflozin and tofogliflozin), CVD outcomes trials (EMPAREG-OUTCOME, CANVAS and DECLARE-TIMI 58) and real-world evidence studies (CVD-REAL, EASEL, CVD-REAL 2 and OBSERVE-4D). A series of clinical recommendations on the use of SGLT-2 inhibitors in Asian patients with T2DM was deliberated among experts with multiple rounds of review and voting. Based on the available evidence, we conclude that SGLT-2 inhibitors represent an evidence-based therapeutic option for the primary prevention of heart failure hospitalization and secondary prevention of CVD in patients with T2DM, and should be considered early on in the treatment algorithm for patients with multiple risk factors, or those with established CVD.
Project description:The purpose is to review evidence on cardiovascular risks and benefits of new treatments for type 2 diabetes mellitus.In response to guidance issued by the Food and Drug Administration, thousands of patients have been enrolled in large randomized trials evaluating the cardiovascular effects of the three newest diabetes drug classes: glucagon-like peptide-1 (GLP-1) receptor agonists, sodium glucose cotransporter 2 (SGLT-2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors. Two studies of GLP-1 receptor agonists-one of liraglutide and one of semaglutide-have shown cardiovascular benefit relative to placebo, and one study of the SGLT-2 inhibitor empagliflozin has shown benefit. The other published cardiovascular outcome studies of the newest drug classes have generally supported safety, apart from an as-yet unresolved safety concern about increased rates of heart failure with DPP-4 inhibitors. Recent research suggests the thiazolidinedione pioglitazone may have beneficial effects on some cardiovascular outcomes as well, but these are counterbalanced by a known increase of the risk of heart failure with this drug. In general, more prospective randomized trial data is now available regarding the cardiovascular effects of the newer diabetes drugs than on the older drug classes. New evidence suggests that the newest diabetes drugs are safe from a cardiovascular perspective. Evidence on benefit from at least some members of the GLP-1 receptor agonist and SGLT-2 inhibitor classes is encouraging but not yet decisive.
Project description:Generalizability of findings from cardiovascular outcomes trials (CVOTs) to patients with type 2 diabetes (T2D) in clinical practice is unknown. We assessed the proportions of patients in the Diabetes Collaborative Registry who would have met enrolment criteria for pivotal CVOTs of sodium-glucose co-transporter-2 inhibitors (SGLT-2is): EMPA-REG OUTCOME, CANVAS, DECLARE and VERTIS CV. In 172 643 patients, mean [standard deviation (SD)] age and HbA1c were 68.1 (11.8) years and 7.8% (2.2), respectively; 56.8% of patients were men and SGLT-2i use was 4.4%. Atherosclerotic cardiovascular disease (ASCVD) prevalence was 64.3% and mean 10-year ASCVD risk was 28.6% in patients without ASCVD. Proportions of patients eligible for CVOTs ranged from 26% (EMPA-REG OUTCOME) to 44% (DECLARE); 48% of patients were ineligible for all CVOTs. Mean (SD) ASCVD risk was 25.4% (22.6), 32.1% (20.6) and 37.7% (19.4) in patients eligible for no, one or two CVOTs, respectively. SGLT-2i use was low in patients eligible for no CVOTs (3.5%) and at least one CVOT (5.2%). In conclusion, applicability of CVOT results to patients with T2D in clinical practice varies based on trial eligibility criteria.