Research Spotlight

Posted May 15th 2020

Cardiovascular Outcomes Among Patients with Type 2 Diabetes Newly Initiated on Sodium-Glucose Cotransporter-2 Inhibitors, Glucagon-Like Peptide-1 Receptor Agonists, and Other Antidiabetic Medications.

Jeffrey B. Michel M.D.

Jeffrey B. Michel M.D.

Pineda, E. D., I. C. Liao, P. J. Godley, J. B. Michel and K. L. Rascati (2020). “Cardiovascular Outcomes Among Patients with Type 2 Diabetes Newly Initiated on Sodium-Glucose Cotransporter-2 Inhibitors, Glucagon-Like Peptide-1 Receptor Agonists, and Other Antidiabetic Medications.” J Manag Care Spec Pharm 26(5): 610-618.

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BACKGROUND: Cardiovascular disease (CVD) remains the most prevalent cause of morbidity and mortality in patients with type 2 diabetes (T2D) and is a primary driver for health care costs associated with diabetes management. Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated significant reductions in cardiovascular endpoints in clinical trials compared with placebo. However, it is uncertain whether these findings can be applied to the broader T2D population because these trials specifically included high-risk patients with established CVD. OBJECTIVE: To evaluate and compare cardiovascular outcomes among adults with T2D newly initiated on SGLT-2is, GLP-1 RAs, and other antidiabetic medications (oADMs) in a real-world setting. METHODS: This retrospective new-user cohort study used administrative claims and electronic health record data from an integrated delivery network in Texas. Patients aged >/=18 years with T2D and >/=1 prescription claim for an SGLT-2i, a GLP-1 RA, or an oADM filled between April 2013 and December 2018 were included. Patients were divided into three 1:1 propensity-matched groups according to index medication identified. Primary outcomes were heart failure hospitalization and a composite end-point of myocardial infarction, stroke, unstable angina, or coronary revascularization. Cox proportional hazards regression was used to compare cumulative incidence of all outcome variables. RESULTS: Among 9,477 patients, 1,134 were initiated on SGLT-2is, 1,072 on GLP-1 RAs, and 7,271 on oADMs. Patients initiating SGLT-2is versus oADMs had significantly lower risk of the composite endpoint (HR = 0.64, 95% CI = 0.46-0.90), heart failure hospitalization (HR = 0.56, 95% CI = 0.39-0.81), and unstable angina requiring hospitalization (HR = 0.56, 95% CI = 0.39-0.81). Patients initiating GLP-1 RAs compared with oADMs had significantly lower risk of the composite endpoint (HR = 0.71, 95% CI = 0.52-0.98) and unstable angina requiring hospitalization (HR = 0.60, 95% CI = 0.41-0.86). No differences in cardiovascular outcomes were found between SGLT-2is and GLP-1 RAs. CONCLUSIONS: Both SGLT-2is and GLP-1 RAs showed significant reductions in the composite outcome and unstable angina requiring hospitalization versus oADMs. However, only SGLT-2is were associated with a lower risk for heart failure hospitalizations. Nevertheless, cardiovascular outcomes were similar between SGLT-2is and GLP-1 RAs. DISCLOSURES: No outside funding supported this study. The authors have no conflicts of interest to report.


Posted May 15th 2020

Echocardiographic Results of Transcatheter Versus Surgical Aortic Valve Replacement in Low-Risk Patients: The PARTNER 3 Trial.

David L. Brown M.D.

David L. Brown M.D.

Pibarot, P., E. Salaun, A. Dahou, E. Avenatti, E. Guzzetti, M. S. Annabi, O. Toubal, M. Bernier, J. Beaudoin, G. Ong, J. Ternacle, L. Krapf, V. H. Thourani, R. Makkar, S. K. Kodali, M. Russo, S. R. Kapadia, S. C. Malaisrie, D. J. Cohen, J. Leipsic, P. Blanke, M. R. Williams, J. M. McCabe, D. L. Brown, V. Babaliaros, S. Goldman, W. Y. Szeto, P. Genereux, A. Pershad, M. C. Alu, K. Xu, E. Rogers, J. G. Webb, C. R. Smith, M. J. Mack, M. B. Leon and R. T. Hahn (2020). “Echocardiographic Results of Transcatheter Versus Surgical Aortic Valve Replacement in Low-Risk Patients: The PARTNER 3 Trial.” Circulation Apr 10. [Epub ahead of print].

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Background: The objective of this study is to compare echocardiographic findings in low risk patients with severe aortic stenosis (AS) following surgical (SAVR) or transcatheter aortic valve replacement (TAVR). Methods: The Placement of Aortic Transcatheter Valves 3 (PARTNER 3) trial randomized 1000 patients with severe AS and low surgical risk to undergo either transfemoral TAVR with the balloon-expandable SAPIEN 3 valve or SAVR. Transthoracic echocardiograms obtained at baseline, and at 30 days and 1 year post-procedure were analyzed by a consortium of 2 echocardiography core laboratories. Results: The percentage of moderate/severe aortic regurgitation (AR) was low and not statistically different between TAVR vs. SAVR groups (30 days: 0.8% vs. 0.2%; p=0.38). However, mild AR was more frequent following TAVR vs. SAVR (30 days: 28.8% vs. 4.2 %; p<0.001). At 1 year, mean transvalvular gradient (13.7+/-5.6 vs. 11.6+/-5.0 mmHg; p=0.12) and aortic valve area (1.72+/-0.37 vs. 1.76+/-0.42 cm(2); p=0.12) were similar in TAVR vs. SAVR. The percentage of severe prosthesis-patient mismatch (PPM) at 30 days was low and similar between TAVR and SAVR (4.6 vs. 6.3%, p=0.30). Valvulo-arterial impedance (Zva), which reflects total left ventricular hemodynamic burden, was lower with TAVR vs. SAVR at 1 year (3.7+/-0.8 vs. 3.9+/-0.9 mmHg/mL/m(2) ; p<0.001). Tricuspid annulus plane systolic excursion (TAPSE) decreased and the percentage of moderate/severe tricuspid regurgitation increased from baseline to 1 year in SAVR, whereas remained unchanged in TAVR. Irrespective of treatment arm, high Zva and low TAPSE, but not moderate/severe AR or severe PPM, were associated with increased risk of the composite endpoint of mortality, stroke and re-hospitalization at 1 year. Conclusions: In patients with severe AS and low surgical risk, TAVR with the SAPIEN 3 valve was associated with similar percentage of moderate/severe AR compared with SAVR, but higher percentage of mild AR. Transprosthetic gradients, valve areas, percentage of severe PPM, and LV mass regression were similar in TAVR versus SAVR. SAVR was associated with significant deterioration of RV systolic function and greater tricuspid regurgitation, which persisted at 1 year. High Zva and low TAPSE were associated with worse outcome at 1 year whereas AR or severe PPM were not.


Posted May 15th 2020

Cerebral cavernous malformation 3 relieves subarachnoid hemorrhage-induced neuroinflammation in rats through inhibiting NF-kB signaling pathway.

Dongxia Feng, M.D.

Dongxia Feng, M.D.

Peng, W., X. Wu, D. Feng, Y. Zhang, X. Chen, C. Ma, H. Shen, X. Li, H. Li, J. Zhang and G. Chen (2020). “Cerebral cavernous malformation 3 relieves subarachnoid hemorrhage-induced neuroinflammation in rats through inhibiting NF-kB signaling pathway.” Brain Res Bull 160: 74-84.

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Subarachnoid hemorrhage (SAH) is a severe acute cerebrovascular disease with high rates of disability and death. In recent years, a large number of studies has shown that early brain injury (EBI) may be a crucial cause of the poor prognosis of SAH and that microglia-mediated neuroinflammation is an important pathological process in EBI. Previous studies have indicated that tumor necrosis factor receptor-associated factor 6 (TRAF6) is involved in microglia-mediated neuroinflammation after SAH. In addition, it has been reported that cerebral cavernous malformation 3/mammalian sterile20-like kinase 4 (CCM3/MST4) directly phosphorylates TRAF6 to inhibit its ubiquitination and to limit inflammatory responses. However, the association between CCM3/MST4 and SAH has not been reported. In our present study, we established a SAH model in adult male rats through injecting autologous arterial blood into the prechiasmatic cistern. Additionally, BV-2 cells, as well as primary microglial cultures from rats treated with oxygen hemoglobin (OxyHb) for 24 h, were used as in vitro models of SAH. Then, western blot, immunofluorescence, Fluoro-JadeC staining and Enzyme-linked immunosorbent assay (ELISA) and behavioral tests was applied in this study. We observed no significant change in the level of CCM3/MST4 in brain tissues, but a markedly decline of CCM3 in microglia of rats. We also found that the protein level of CCM3 was decreased in BV-2 cells after OxyHb treatment, reaching the lowest point at 6 h post-treatment. In contrast, there was no significant change in the protein level of MST4. Additionally, we recapitulated decreased expression of CCM3 and changes in subcellular localization of CCM3 in vitro model of SAH with primary microglial cultures treated with OxyHb. Overexpression of CCM3 decreased cellular degeneration, neurocognitive impairment, NF-kappaB p65 level in the nuclear, and inflammatory factors level (TNF-a and IL-1beta). These results suggest that overexpression of CCM3 alleviated brain injury and neurological damage through the NF-kappaB signaling pathway.


Posted May 15th 2020

Long-term efficacy and safety of brodalumab in psoriasis through 120 weeks and after withdrawal and retreatment: subgroup analysis of a randomised phase 3 trial (AMAGINE-1).

Alan M. Menter M.D.

Alan M. Menter M.D.

Papp, K., A. Menter, C. Leonardi, J. Soung, S. Weiss, R. Pillai and A. Jacobson (2020). “Long-term efficacy and safety of brodalumab in psoriasis through 120 weeks and after withdrawal and retreatment: subgroup analysis of a randomised phase 3 trial (AMAGINE-1).” Br J Dermatol Apr 14. [Epub ahead of print].

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BACKGROUND: Brodalumab is efficacious for the treatment of moderate-to-severe plaque psoriasis through 52 weeks. OBJECTIVE: To evaluate the efficacy and safety of brodalumab through 120 weeks, including following withdrawal and retreatment. METHODS: At baseline, patients were randomized to brodalumab (n=222) or placebo (n=220). At week 12, patients achieving static physician’s global assessment score of 0 or 1 (sPGA 0/1) with brodalumab were re-randomized to brodalumab (n=83) or placebo (n=84; later re-treated with brodalumab if sPGA >/=3 occurred), and patients receiving placebo switched to brodalumab (n=208). Safety was assessed by treatment-emergent adverse events. RESULTS: Among those who achieved sPGA 0/1 at week 12 and were re-randomized to brodalumab, 95.7% and 79.5% using observed data, respectively, and 73.9% and 61.4% using nonresponder imputation, respectively, achieved 75% improvement in psoriasis area and severity index (PASI 75) and PASI 100 at week 120. Following withdrawal from brodalumab, return of disease occurred after a mean (standard deviation) of 74.7 (50.5) days. Among those who switched from brodalumab to placebo at week 12, PASI 75 rates using observed data and nonresponder imputation were 55.1% and 51.2% at week 20, respectively, and 94.0% and 75.0% at week 120, respectively; PASI 100 rates at week 120 were 74.6% and 59.5%, respectively. Efficacy was maintained through week 120 in those receiving brodalumab after placebo. No new safety signals were observed. CONCLUSIONS: These findings indicate that brodalumab is efficacious and safe for continuous long-term treatment of psoriasis and support potential for response after discontinuation and retreatment.


Posted May 15th 2020

Role of Impaired Nutrient and Oxygen Deprivation Signaling and Deficient Autophagic Flux in Diabetic CKD Development: Implications for Understanding the Effects of Sodium-Glucose Cotransporter 2-Inhibitors.

Milton Packer M.D.

Milton Packer M.D.

Packer, M. (2020). “Role of Impaired Nutrient and Oxygen Deprivation Signaling and Deficient Autophagic Flux in Diabetic CKD Development: Implications for Understanding the Effects of Sodium-Glucose Cotransporter 2-Inhibitors.” J Am Soc Nephrol 31(5): 907-919.

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Growing evidence indicates that oxidative and endoplasmic reticular stress, which trigger changes in ion channels and inflammatory pathways that may undermine cellular homeostasis and survival, are critical determinants of injury in the diabetic kidney. Cells are normally able to mitigate these cellular stresses by maintaining high levels of autophagy, an intracellular lysosome-dependent degradative pathway that clears the cytoplasm of dysfunctional organelles. However, the capacity for autophagy in both podocytes and renal tubular cells is markedly impaired in type 2 diabetes, and this deficiency contributes importantly to the intensity of renal injury. The primary drivers of autophagy in states of nutrient and oxygen deprivation-sirtuin-1 (SIRT1), AMP-activated protein kinase (AMPK), and hypoxia-inducible factors (HIF-1alpha and HIF-2alpha)-can exert renoprotective effects by promoting autophagic flux and by exerting direct effects on sodium transport and inflammasome activation. Type 2 diabetes is characterized by marked suppression of SIRT1 and AMPK, leading to a diminution in autophagic flux in glomerular podocytes and renal tubules and markedly increasing their susceptibility to renal injury. Importantly, because insulin acts to depress autophagic flux, these derangements in nutrient deprivation signaling are not ameliorated by antihyperglycemic drugs that enhance insulin secretion or signaling. Metformin is an established AMPK agonist that can promote autophagy, but its effects on the course of CKD have been demonstrated only in the experimental setting. In contrast, the effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors may be related primarily to enhanced SIRT1 and HIF-2alpha signaling; this can explain the effects of SGLT2 inhibitors to promote ketonemia and erythrocytosis and potentially underlies their actions to increase autophagy and mute inflammation in the diabetic kidney. These distinctions may contribute importantly to the consistent benefit of SGLT2 inhibitors to slow the deterioration in glomerular function and reduce the risk of ESKD in large-scale randomized clinical trials of patients with type 2 diabetes.