Diabetic Nephropathy: Update on Pillars of Therapy Slowing Progression.

Management of diabetic kidney disease (DKD) has evolved in parallel with our growing understanding of the multiple interrelated pathophysiological mechanisms that involve hemodynamic, metabolic, and inflammatory pathways. These pathways and others play a vital role in the initiation and progression of DKD. Since its initial discovery, the blockade of the renin-angiotensin system has remained a cornerstone of DKD management, leaving a large component of residual risk to be dealt with. The advent of sodium-glucose cotransporter 2 inhibitors followed by nonsteroidal mineralocorticoid receptor antagonists and, to some extent, glucagon-like peptide 1 receptor agonists (GLP-1 RAs) has ushered in a resounding paradigm shift that supports a pillared approach in maximizing treatment to reduce outcomes. This pillared approach is like that derived from the approach to heart failure treatment. The approach mandates that all agents that have been shown in clinical trials to reduce cardiovascular outcomes and/or mortality to a greater extent than a single drug class alone should be used in combination. In this way, each drug class focuses on a specific aspect of the disease's pathophysiology. Thus, in heart failure, ß-blockers, sacubitril/valsartan, a mineralocorticoid receptor antagonist, and a diuretic are used together. In this article, we review the evolution of the pillar concept of therapy as it applies to DKD and discuss how it should be used based on the outcome evidence. We also discuss the exciting possibility that GLP-1 RAs may be an additional pillar in the quest to further slow kidney disease progression in diabetes.

Obesity and Breast Cancer Risk: The Oncogenic Implications of Metabolic Dysregulation.

CONTEXT: Breast cancer is increasing in prevalence in parallel with rising rates of obesity worldwide. Obesity is recognized as a leading modifiable risk factor for the development of breast cancer; however, this association varies considerably by clinicopathologic features, and the underlying mechanisms are complex. EVIDENCE ACQUISITION: Pubmed literature search using combinations of "obesity," "breast cancer risk," "diet," "exercise," "weight gain," "weight loss," "adipose tissue inflammation," "crown-like structure," "immune markers," "metformin," "gliflozins," "SGLT-2i," "GLP1-RA," and related terms. EVIDENCE SYNTHESIS: Elevated body mass index and weight gain are associated with increased risk of postmenopausal, hormone receptor-positive breast cancer. Emerging evidence suggests that adverse measures of body composition in individuals of any weight can also confer increased breast cancer risk. Mechanistically, various factors including altered adipokine balance, dysfunctional adipose tissue, dysregulated insulin signaling, and chronic inflammation contribute to tumorigenesis. Weight loss and more specifically fat mass loss through lifestyle and pharmacologic interventions improve serum metabolic and inflammatory markers, sex hormone levels, and measures of breast density, suggesting a link to decreased breast cancer risk. CONCLUSION: Incorporating markers of metabolic health and body composition measures with body mass index can capture breast cancer risk more comprehensively. Further studies of interventions targeting body fat levels are needed to curb the growing prevalence of obesity-related cancer.

Denosumab Discontinuation in Patients Treated for Low Bone Density and Osteoporosis.

Denosumab (DMAB) is a potent antiresorptive treatment used for treatment of osteoporosis and low bone mineral density (BMD) in those at high risk for fracture. In postmenopausal women with osteoporosis, DMAB treatment for 10 years has been studied, with results showing continued gains in BMD, sustained fracture risk reduction, and low risk of adverse events. However, upon discontinuation of DMAB, there is a rapid reversal of effect, with increase in bone turnover, loss of BMD, and in a subset of patients, a greater risk for multiple vertebral fractures.

Status of psychological trials in breast cancer patients: a report of three meta-analyses.

This systematic review reports the results of three meta-analyses addressing the clinical efficacy of psychological interventions in breast cancer patients. Three outcome variables were examined: anxiety, depression and quality of life. Several moderator variables were found to both account for inter-trial heterogeneity and interact with treatment efficacy; methodological quality, prognosis, treatment type, orientation and duration. A clinically moderate treatment effect was found for anxiety (-0.40, 95% CI, -0.72 to -0.08, N = 1278). This was not robust to study quality, but remained stable for patients with more advanced disease. Short-term group therapy was more effective than longer term intervention and individual ones. A clinically moderate-to-strong effect was found in trials assessing depression (-1.01, 95% CI, -1.48 to -0.54, N = 1324). A more robust finding of -0.47 (95% -0.69 to -0.24) was based on methodologically more reliable studies treating patients with high psychological morbidity. Intervention was shown to have moderate effects on improving QOL (0.74, 95% CI, 0.12 to 1.37, N = 623), though it was not robust to study quality. Findings suggest that short-term treatments with a focus on coping may be more suitable for early breast cancer patients. Patients with advanced breast disease appear to benefit more from longer term interventions which emphasize support. Recommendations are also made for future clinical trials.