Research Spotlight

Packer, M. (2020). “Molecular, Cellular, and Clinical Evidence That Sodium-Glucose Cotransporter 2 Inhibitors Act as Neurohormonal Antagonists When Used for the Treatment of Chronic Heart Failure.” J Am Heart Assoc 9(16): e016270.

Full text of this article.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure. Initially, these drugs were believed to have a profile similar to diuretics or hemodynamically active drugs, but they do not rapidly reduce natriuretic peptides or cardiac filling pressures, and they exert little early benefit on symptoms, exercise tolerance, quality of life, or signs of congestion. Clinically, the profile of SGLT2 inhibitors resembles that of neurohormonal antagonists, whose benefits emerge gradually during sustained therapy. In experimental models, SGLT2 inhibitors produce a characteristic pattern of cellular effects, which includes amelioration of oxidative stress, mitigation of mitochondrial dysfunction, attenuation of proinflammatory pathways, and a reduction in myocardial fibrosis. These cellular effects are similar to those produced by angiotensin converting enzyme inhibitors, β-blockers, mineralocorticoid receptor antagonists, and neprilysin inhibitors. At a molecular level, SGLT2 inhibitors induce transcriptional reprogramming of cardiomyocytes that closely mimics that seen during nutrient deprivation. This shift in signaling activates the housekeeping pathway of autophagy, which clears the cytosol of dangerous cytosolic constituents that are responsible for cellular stress, thereby ameliorating the development of cardiomyopathy. Interestingly, similar changes in cellular signaling and autophagic flux have been seen with inhibitors of the renin-angiotensin system, β-blockers, mineralocorticoid receptor antagonists, and neprilysin inhibitors. The striking parallelism of these molecular, cellular, and clinical profiles supports the premise that SGLT2 inhibitors should be regarded as neurohormonal antagonists when prescribed for the treatment of heart failure with a reduced ejection fraction.

Packer, M. (2020). “Role of ketogenic starvation sensors in mediating the renal protective effects of SGLT2 inhibitors in type 2 diabetes.” J Diabetes Complications 34(9): 107647.

Full text of this article.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ameliorate the progression of diabetic chronic kidney disease, but the mechanisms underlying this nephroprotective effect have not been fully elucidated. These drugs induce a fasting-like transcriptional paradigm, which includes activation of sirtuin-1 (SIRT1) and its downstream effectors, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and fibroblast growth factor 21 (FGF21). This triad of enzymes and transcription factors serve as master regulators of nutrient and cellular homeostasis, and each acts to enhance gluconeogenesis, fatty acid oxidation and ketogenesis, the hallmarks of treatment with SGLT2 inhibitors. At the same time, SIRT1/PGC-1α/FGF21 signaling also promotes autophagy, a lysosome-dependent degradative pathway that cleanses the cytosol of dysfunctional organelles. This action alleviates cellular stress, ameliorates inflammation, and is strikingly nephroprotective. Interestingly, type 2 diabetes is characterized by both a deficiency of SIRT1/PGC-1α signaling and an impairment of autophagic flux, thus explaining the high levels of oxidative stress in the diabetic kidney. SIRT1 gene polymorphisms have been linked with an increased risk of diabetic nephropathy in several epidemiological studies. Importantly, there is an inverse relationship between the activity of SGLT2 and signaling through the SIRT1/PGC-1α/FGF21 pathway, and SGLT2 inhibition leads to activation of these ketogenic nutrient deprivation sensors. Therefore, activation of SIRT1/PGC-1α/FGF21 may explain the effect of SGLT2 inhibitors not only to promote ketogenesis, but also to preserve renal function in type 2 diabetes.

Rugo, H.S., Dieras, V., Cortes, J., Patt, D., Wildiers, H., O’Shaughnessy, J., Zamora, E., Yardley, D.A., Carter, G.C., Sheffield, K.M., Li, L., Andre, V.A.M., Li, X.I., Frenzel, M., Huang, Y.J., Dickler, M.N. and Tolaney, S.M. (2020). “Real-world survival outcomes of heavily pretreated patients with refractory HR+, HER2-metastatic breast cancer receiving single-agent chemotherapy-a comparison with MONARCH 1.” Breast Cancer Res Treat Aug 12. [Epub ahead of print.].

Full text of this article.

PURPOSE: In MONARCH 1 (NCT02102490), single-agent abemaciclib demonstrated promising efficacy activity and tolerability in a population of heavily pretreated women with refractory HR+, HER2- metastatic breast cancer (MBC). To help interpret these results and put in clinical context, we compared overall survival (OS) and duration of therapy (DoT) between MONARCH 1 and a real-world single-agent chemotherapy cohort. METHODS: The real-world chemotherapy cohort was created from a Flatiron Health electronic health records-derived database based on key eligibility criteria from MONARCH 1. The chemotherapies included in the cohort were single-agent capecitabine, gemcitabine, eribulin, or vinorelbine. Results were adjusted for baseline demographics and clinical differences using Mahalanobis distance matching (primary analysis) and entropy balancing (sensitivity analysis). OS and DoT were analyzed using the Kaplan-Meier method and Cox proportional hazards regression. RESULTS: A real-world single-agent chemotherapy cohort (n = 281) with eligibility criteria similar to the MONARCH 1 population (n = 132) was identified. The MONARCH 1 (n = 108) cohort was matched to the real-world chemotherapy cohort (n = 108). Median OS was 22.3 months in the abemaciclib arm versus 13.6 months in the matched real-world chemotherapy cohort with an estimated hazard ratio (HR) of 0.54. The median DoT was 4.1 months in MONARCH 1 compared to 2.9 months in the real-world chemotherapy cohort with HR of 0.76. CONCLUSIONS: This study demonstrates an approach to create a real-world chemotherapy cohort suitable to serve as a comparator for trial data. These exploratory results suggest a survival advantage and place the benefit of abemaciclib monotherapy in clinical context.

Iversen, L., Kurvits, M., Snel-Prentø, A.M. and Menter, A. (2020). “Calcipotriol/Betamethasone Dipropionate Cutaneous Foam Treatment for Psoriasis in Patients With BSA 5-15% and PGA ≥ 3: Post-Hoc Analysis From Three Randomized Controlled Trials.” Dermatol Ther (Heidelb) 10(5): 1111-1120.

Full text of this article.

INTRODUCTION: Psoriasis is a chronic, inflammatory disease, which ranges in severity from mild to severe. Although topical therapies are frequently used to treat mild disease, they are not routinely used to treat patients with moderate-to-severe disease who have a larger proportion of their body surface area (BSA) affected (≥ 5% BSA). Based on well-controlled trials in adults with mild-to-severe disease, fixed-dose combination calcipotriol 50 μg/g + betamethasone dipropionate 0.5 mg/g (Cal/BD) cutaneous foam has been approved (Enstilar®, LEO Pharma) in the USA and EU for the treatment of psoriasis vulgaris for up to 4 weeks in adults. In this post-hoc subgroup analysis, we used pooled data from phase II/III trials to investigate the efficacy and safety of Cal/BD cutaneous foam in patients with moderate-to-severe psoriasis. METHODS: Patients included in this analysis had psoriasis affecting 5-15% BSA and a physician’s global assessment (PGA) ≥ 3. Endpoints included: treatment success by PGA (rating: clear/almost clear), patient’s global assessment (PaGA) at week 4 (rating: clear/very mild) and safety. RESULTS: A total of 340 patients in the three randomized trials met the BSA/PGA inclusion criteria, of whom 254 were treated with Cal/BD foam and 86 with vehicle foam. Treatment success by PGA and PaGA at week 4 was achieved in 143 (58.1%) and 138 (56.1%) patients receiving Cal/BD foam, respectively, versus three (3.6%) and 14 (16.7%) patients receiving vehicle foam. Sixty-six adverse events (AEs) occurred in 47 (18.5%) patients receiving Cal/BD foam and 11 AEs occurred in 11 (12.8%) patients receiving vehicle foam. Three severe AEs and 15 non-serious treatment-related AEs occurred in patients receiving Cal/BD foam. CONCLUSION: The results from three clinical trials analyzed together show that topical Cal/BD foam is well tolerated and efficacious for treating patients with moderate-to-severe disease. Data support Cal/BD foam as a potential topical therapy for moderate-to-severe psoriasis.

Yoon, S.H., Kim, W.K., Dhoble, A., Milhorini Pio, S., Babaliaros, V., Jilaihawi, H., Pilgrim, T., De Backer, O., Bleiziffer, S., Vincent, F., Schmidit, T., Butter, C., Kamioka, N., Eschenbach, L., Renker, M., Asami, M., Lazkani, M., Fujita, B., Birs, A., Barbanti, M., Pershad, A., Landes, U., Oldemeyer, B., Kitamura, M., Oakley, L., Ochiai, T., Chakravarty, T., Nakamura, M., Ruile, P., Deuschl, F., Berman, D., Modine, T., Ensminger, S., Kornowski, R., Lange, R., McCabe, J.M., Williams, M.R., Whisenant, B., Delgado, V., Windecker, S., Van Belle, E., Sondergaard, L., Chevalier, B., Mack, M., Bax, J.J., Leon, M.B. and Makkar, R.R. (2020). “Bicuspid Aortic Valve Morphology and Outcomes After Transcatheter Aortic Valve Replacement.” J Am Coll Cardiol 76(9): 1018-1030.

Full text of this article.

BACKGROUND: Bicuspid aortic stenosis accounts for almost 50% of patients undergoing surgical aortic valve replacement in the younger patients. Expanding the indication of transcatheter aortic valve replacement (TAVR) toward lower-risk and younger populations will lead to increased use of TAVR for patients with bicuspid aortic valve (BAV) stenosis despite the exclusion of bicuspid anatomy in all pivotal clinical trials. OBJECTIVES: This study sought to evaluate the association of BAV morphology and outcomes of TAVR with the new-generation devices. METHODS: Patients with BAV confirmed by central core laboratory computed tomography (CT) analysis were included from the international multicenter BAV TAVR registry. BAV morphology including the number of raphe, calcification grade in raphe, and leaflet calcium volume were assessed with CT analysis in a masked fashion. Primary outcomes were all-cause mortality at 1 and 2 years, and secondary outcomes included 30-day major endpoints and procedural complications. RESULTS: A total of 1,034 CT-confirmed BAV patients with a mean age of 74.7 years and Society of Thoracic Surgeons score of 3.7% underwent TAVR with contemporary devices (n = 740 with Sapien 3; n = 188 with Evolut R/Pro; n = 106 with others). All-cause 30-day, 1-year, and 2-year mortality was 2.0%, 6.7%, and 12.5%, respectively. Multivariable analysis identified calcified raphe and excess leaflet calcification (defined as more than median calcium volume) as independent predictors of 2-year all-cause mortality. Both calcified raphe plus excess leaflet calcification were found in 269 patients (26.0%), and they had significantly higher 2-year all-cause mortality than those with 1 or none of these morphological features (25.7% vs. 9.5% vs. 5.9%; log-rank p < 0.001). Patients with both morphological features had higher rates of aortic root injury (p < 0.001), moderate-to-severe paravalvular regurgitation (p = 0.002), and 30-day mortality (p = 0.016). CONCLUSIONS: Outcomes of TAVR in bicuspid aortic stenosis depend on valve morphology. Calcified raphe and excess leaflet calcification were associated with increased risk of procedural complications and midterm mortality. (Bicuspid Aortic Valve Stenosis Transcatheter Aortic Valve Replacement Registry; NCT03836521).