Patients with chronic kidney disease (CKD) exhibit an elevated cardiovascular risk manifesting as coronary artery disease, heart failure, arrhythmias, and sudden cardiac death. Although the incidence and prevalence of cardiovascular events is already significantly higher in patients with early CKD stages (CKD stages 1–3) compared with the general population, patients with advanced CKD stages (CKD stages 4–5) exhibit a markedly elevated risk. Cardiovascular rather than end-stage kidney disease (CKD stage 5) is the leading cause of death in this high-risk population. CKD causes a systemic, chronic proinflammatory state contributing to vascular and myocardial remodeling processes resulting in atherosclerotic lesions, vascular calcification, and vascular senescence as well as myocardial fibrosis and calcification of cardiac valves. In this respect, CKD mimics an accelerated aging of the cardiovascular system. This overview article summarizes the current understanding and clinical consequences of cardiovascular disease in CKD.

When choosing medications to manage type 2 diabetes, cardiovascular safety, glucose-lowering potency, hypoglycemia risk, effect on body weight, and cost are important considerations.^1-3 Most guidelines state that metformin should be first-line therapy followed by various options for second-line treatment if sufficient glycemic control is not achieved after metformin monotherapy.^1-3 Sulfonylureas and dipeptidyl peptidase-4 (DPP-4) inhibitors are the most commonly used second-line glucose-lowering treatments in many countries.⁴ Sulfonylureas are used mainly based on their low cost, well-established glucose-lowering action, and a long-standing experience in clinical practice. However, sulfonylureas are associated with increased risk of hypoglycemia^1,3,5-7 and modest weight gain.^1,5 In addition, there is an ongoing controversy regarding their long-term cardiovascular safety, based on early data from the University Group Diabetes Program in the 1960s⁸ and multiple observational and smaller studies indicating conflicting results.^9,10

Patients with type 2 diabetes are at high risk for development of cardiovascular disease, including myocardial infarction, stroke, heart failure, and cardiovascular death. Multiple large cardiovascular outcome trials with novel glucose-lowering agents, namely SGLT2i (SGLT2 inhibitors) and GLP-1 RA (GLP-1 receptor agonists), have demonstrated robust and significant reductions of major adverse cardiovascular events and additional cardiovascular outcomes, such as hospitalizations for heart failure. This evidence has changed the landscape for treatment of patients with type 2 diabetes. Both diabetes and cardiology guidelines and professional societies have responded to this paradigm shift by including strong recommendations to use SGLT2i and/or GLP-1 RA, with evidence-based benefits to reduce cardiovascular risk in high-risk individuals with type 2 diabetes, independent of the need for additional glucose control. GLP-1 RA were initially developed as glucose-lowering drugs because activation of the GLP-1 receptor by these agents leads to a reduction in blood glucose and an improvement in postprandial glucose metabolism. By stimulating GLP-1R in hypothalamic neurons, GLP-1 RA additionally induce satiety and lead to weight loss. Data from cardiovascular outcome trials demonstrated a robust and consistent reduction in atherothrombotic events, particularly in patients with established atherosclerotic cardiovascular disease. Despite the consistent evidence of atherosclerotic cardiovascular disease benefit from these trials, the number of patients receiving these drugs remains low. This overview summarizes the experimental and clinical evidence of cardiovascular risk reduction offered by GLP-1 RA, and provides practical information on how these drugs should be implemented in the treatment of type 2 diabetes in the cardiology community.

The global prevalence of obesity has more than doubled over the past four decades, currently affecting more than a billion individuals. Beyond its recognition as a high-risk condition that is causally linked to many chronic illnesses, obesity has been declared a disease per se that results in impaired quality of life and reduced life expectancy. Notably, two-thirds of obesity-related excess mortality is attributable to cardiovascular disease. Despite the increasingly appreciated link between obesity and a broad range of cardiovascular disease manifestations including atherosclerotic disease, heart failure, thromboembolic disease, arrhythmias, and sudden cardiac death, obesity has been underrecognized and sub-optimally addressed compared with other modifiable cardiovascular risk factors. In the view of major repercussions of the obesity epidemic on public health, attention has focused on population-based and personalized approaches to prevent excess weight gain and maintain a healthy body weight from early childhood and throughout adult life, as well as on comprehensive weight loss interventions for persons with established obesity. This clinical consensus statement by the European Society of Cardiology discusses current evidence on the epidemiology and aetiology of obesity; the interplay between obesity, cardiovascular risk factors and cardiac conditions; the clinical management of patients with cardiac disease and obesity; and weight loss strategies including lifestyle changes, interventional procedures, and anti-obesity medications with particular focus on their impact on cardiometabolic risk and cardiac outcomes. The document aims to raise awareness on obesity as a major risk factor and provide guidance for implementing evidence-based practices for its prevention and optimal management within the context of primary and secondary cardiovascular disease prevention.

Background: Sodium-glucose cotransporter 2 inhibitors improve outcomes in patients with heart failure with reduced ejection fraction, but additional information is needed about whether glycemic status influences the magnitude of their benefits on heart failure and renal events. Methods: Patients with Class II–IV heart failure and a left ventricular ejection fraction ≤40% were randomized to receive empagliflozin (10 mg daily) or placebo in addition to recommended therapy. We prespecified a comparison of the effect of empagliflozin in patients with and without diabetes. Results: Of the 3730 patients enrolled, 1856 (50%) had diabetes, 1268 (34%) had prediabetes (hemoglobin A1c [HbA1c] 5.7–6.4%), and 606 (16%) had normoglycemia (HbA1c <5.7%). The risks of the primary outcome (cardiovascular death or hospitalization for heart failure), total hospitalizations for heart failure, and adverse renal outcomes were higher in patients with diabetes, but were similar between patients with prediabetes and normoglycemia. Empagliflozin reduced the risk of the primary outcome in patients with and without diabetes (hazard ratio, 0.72 [95% CI, 0.60–0.87] and 0.78 [95% CI, 0.64–0.97], respectively, P -interaction=0.57). Patients with and without diabetes also did not differ with respect to the effect of empagliflozin on total hospitalizations for heart failure, on the decline in estimated glomerular filtration rate over time, and on the risk of serious adverse renal outcomes. Among these end points, the effects of the drug did not differ in patients with prediabetes or normoglycemia. When analyzed as a continuous variable, baseline HbA1c did not significantly modify the benefits of empagliflozin on the primary outcome ( P -interaction=0.40). Empagliflozin did not lower HbA1c in patients with prediabetes or normoglycemia and was not associated with increased risk of hypoglycemia. Conclusions: In EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), empagliflozin significantly improved cardiovascular and renal outcomes in patients with heart failure and a reduced ejection fraction, independent of baseline diabetes status and across the continuum of HbA1c. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03057977.