Search

In people with type 2 diabetes at high risk of cardiovascular or kidney disease, sodium-glucose co-transporter 2 (SGLT2) inhibitors consistently reduce the risk of hospitalisations for heart failure. Less is known about their effects on hospitalisation from any cause, especially in people with type 2 diabetes without atherosclerotic cardiovascular disease, which includes most of the global population of people with type 2 diabetes. We aimed to assess the effect of the SGLT2 inhibitor, dapagliflozin, on the risks of hospitalisations for any cause and for specific causes in people with type 2 diabetes with and without atherosclerotic cardiovascular disease.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are highly effective in reducing glycemia in patients with type 2 diabetes (T2D). These medications effectively reduce cardiovascular (CV) risk in patients with T2D and established CV disease or with multiple risk factors. In addition, treatment with GLP-1 RA may exert protective effects on the diabetic kidney. Herein, we summarize the findings regarding the kidney safety and efficacy of GLP-1 RAs in patients with T2D. We review data from GLP-1 RAs phase 3 kidney studies, CV outcome trials, as well as real-world evidence. The accumulating data show that treatment with GLP-1 RAs is safe, well-tolerated, and effective in patients with different levels of kidney dysfunction. Furthermore, CV outcome trials suggest that GLP-1 RAs reduce albuminuria and may attenuate the decline in kidney function over time. The ongoing FLOW trial studying the effects of semaglutide in patients with diabetic kidney disease is expected to shed light on the effects of GLP-1 RAs on kidney outcomes and clarify their role in the management of patients with T2D and kidney disease.

Recent data support an involvement of defects in homeostasis of phosphoinositides (PIPs) in the pathophysiology of Parkinson’s disease (PD). Genetic mutations have been identified in genes encoding for PIP-regulating and PIP-interacting proteins, that are associated with familial and sporadic PD. Many of these proteins are implicated in vesicular membrane trafficking, mechanisms that were recently highlighted for their close associations with PD. PIPs are phosphorylated forms of the membrane phospholipid, phosphatidylinositol. Their composition in the vesicle’s membrane of origin, as well as membrane of destination, controls vesicular membrane trafficking. We review the converging evidence that points to the involvement of PIPs in PD. The review describes PD- and PIP-associated proteins implicated in clathrin-mediated endocytosis and autophagy, and highlights the involvement of α-synuclein in these mechanisms.

Pain is prevalent among patients with diabetes and chronic kidney disease (CKD). The management of chronic pain in these patients is limited by nephrotoxicity of commonly used drugs including non-steroidal anti-inflammatory drugs (NSAIDs) and opioids. Since previous studies implicated endothelin-1 in pain nociception, our post hocanalysis of the SONAR trial assessed the association between the endothelin receptor antagonist atrasentan and pain and prescription of analgesics. SONAR was a randomized, double-blind, placebo-controlled clinical trial that recruited participants with type 2 diabetes and CKD (estimated glomerular filtration rate 25–75 ml/min/1.73 m2; urinary albumin-to-creatinine ratio 300–5000 mg/g). Participants were randomized to receive atrasentan or placebo (1834 each arm). The main outcome was pain-related adverse events (AEs) reported by investigators. We applied Cox regression to assess the effect of atrasentan compared to placebo on the risk of the first reported pain-related AE and, secondly, first prescription of analgesics. We used the Anderson-Gill method to assess effects on all (first and subsequent) pain-related AEs. During 2.2-year median follow-up, 1183 pain-related AEs occurred. Rates for the first pain-related event were 138.2 and 170.2 per 1000 person-years in the atrasentan and placebo group respectively (hazard ratio 0.82 [95% confidence interval 0.72–0.93]). Atrasentan also reduced the rate of all (first and subsequent) pain-related AEs (rate ratio 0.80 [0.70-0.91]. These findings were similar after accounting for competing risk of death (sub-hazard ratio 0.81 [0.71–0.92]). Patients treated with atrasentan initiated fewer analgesics including NSAIDs and opioids compared to placebo during follow-up (hazard ratio=0.72 [0.60–0.88]). Thus, atrasentan was associated with reduced pain-related events and pain-related use of analgesics in carefully selected patients with type 2 diabetes and CKD.

Background:In the DECLARE-TIMI 58 trial, involving patients with type 2 diabetes at high cardiovascular (CV) risk, dapagliflozin reduced the risk for heart failure hospitalization and adverse kidney outcomes, compared to placebo. Whether dapagliflozin lowers the risks for the broader outcome of adverse event (AE)-related hospital admissions is unknown.Methods:The DECLARE-TIMI 58 trial randomized 17,160 subjects with type 2 diabetes and a high risk for or established CV disease, to receive dapagliflozin or placebo (1:1). Dapagliflozin effect on AE-related hospital admissions was assessed overall and by baseline cardiovascular and kidney subgroups. Investigator reported system organ class classification was used to evaluate dapagliflozin's effects on admissions due to different etiologies.Results:Over a median follow up of 4.2 years, dapagliflozin reduced the risk of AE-related hospital admissions by 11% (32.4% vs. 35.4% of participants, HR 0.89 [95% CI 0.85, 0.94]; p<0.0001). The reduction in AE-related hospital admissions was consistent across baseline cardiovascular and kidney subgroups (p-interaction≥0.30) (Figure). Dapagliflozin reduced the risk for admissions due to cardiac disorders (HR 0.91 [95% CI 0.84,0.995] p=0.0387), renal or urinary disorders (0.61 [0.49, 0.77] p<0.0001), and other non-cardiac, non-renal etiologies (0.89 [0.84,0.95] p=0.0001).Conclusion:Dapagliflozin reduced the risk for AE-related hospital admissions, including non-cardiac and non-renal hospitalizations, in patients with type 2 diabetes. These findings have implications for patients' quality of life and overall type 2 diabetes-attributed healthcare burden.