Research Spotlight

Posted May 15th 2020

Interplay of adenosine monophosphate-activated protein kinase/sirtuin-1 activation and sodium influx inhibition mediates the renal benefits of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes: A novel conceptual framework.

Milton Packer M.D.

Milton Packer M.D.

Packer, M. (2020). “Interplay of adenosine monophosphate-activated protein kinase/sirtuin-1 activation and sodium influx inhibition mediates the renal benefits of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes: A novel conceptual framework.” Diabetes Obes Metab 22(5): 734-742.

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Long-term treatment with sodium-glucose co-transporter-2 (SGLT2) inhibitors slows the deterioration of renal function in patients with diabetes. This benefit cannot be ascribed to an action on blood glucose, ketone utilization, uric acid or systolic blood pressure. SGLT2 inhibitors produce a striking amelioration of glomerular hyperfiltration. Although initially ascribed to an action of these drugs to inhibit proximal tubular glucose reabsorption, SGLT2 inhibitors exert renoprotective effects, even in patients with meaningfully impaired levels of glomerular function that are sufficient to abolish their glycosuric actions. Instead, the reduction in intraglomerular pressures may be related to an action of SGLT2 inhibitors to interfere with the activity of sodium-hydrogen exchanger isoform 3, thereby inhibiting proximal tubular sodium reabsorption and promoting tubuloglomerular feedback. Yet, experimentally, such an effect may not be sufficient to prevent renal injury. It is therefore noteworthy that the diabetic kidney exhibits an important defect in adenosine monophosphate-activated protein kinase (AMPK) and sirtuin-1 (SIRT1) signalling, which may contribute to the development of nephropathy. These transcription factors exert direct effects to mute oxidative stress and inflammation, and they also stimulate autophagy, a lysosomally mediated degradative pathway that maintains cellular homeostasis in the kidney. SGLT2 inhibitors induce both AMPK and SIRT1, and they have been shown to stimulate autophagy, thereby ameliorating cellular stress and glomerular and tubular injury. Enhanced AMPK/SIRT1 signalling may also contribute to the action of SGLT2 inhibitors to interfere with sodium transport mechanisms. The dual effects of SGLT2 inhibitors on AMPK/SIRT1 activation and renal tubular sodium transport may explain the protective effects of these drugs on the kidney in type 2 diabetes.


Posted May 15th 2020

Are the benefits of SGLT2 inhibitors in heart failure and a reduced ejection fraction influenced by background therapy? Expectations and realities of a new standard of care.

Milton Packer M.D.

Milton Packer M.D.

Packer, M. (2020). “Are the benefits of SGLT2 inhibitors in heart failure and a reduced ejection fraction influenced by background therapy? Expectations and realities of a new standard of care.” Eur Heart J Apr 29. pii: ehaa344. [Epub ahead of print].

Full text of this article.

With the completion of two large-scale trials of SGLT2 inhibitors in patients with chronic heart failure and a reduced ejection fraction, we are poised to add yet another drug to our portfolio of cardioprotective agents. These disease-modifying drugs target important, but distinct, pathways that promote cardiomyocyte dysfunction and demise, and it is critical that physicians prescribe all of them in combination to all appropriate patients who do not have demonstrable intolerance. Yet, <1% of patients with chronic heart failure are receiving currently recommended drugs at doses that have been shown to prolong life.1 According to modelling estimates, when compared with no neurohormonal blockade, the use of a broad-based combination of disease-modifying drugs at target doses may reduce the risk of death by as much as 75%. It is time that physicians who treat patients with heart failure took notice. (Excerpt from text; no abstract available.)


Posted May 15th 2020

Cost-effectiveness of surgical treatment of adult spinal deformity: comparison of posterior-only versus anteroposterior approach.

Samrat Yeramaneni Ph.D.

Samrat Yeramaneni Ph.D.

Ogura, Y., J. L. Gum, R. A. Hostin, C. Robinson, C. P. Ames, S. D. Glassman, D. C. Burton, R. S. Bess, C. I. Shaffrey, J. S. Smith, S. Yeramaneni, V. F. Lafage, T. Protopsaltis, P. G. Passias, F. J. Schwab and L. Y. Carreon (2020). “Cost-effectiveness of surgical treatment of adult spinal deformity: comparison of posterior-only versus anteroposterior approach.” Spine J Apr 12. pii: S1529-9430(20)30136-4. [Epub ahead of print].

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BACKGROUND CONTEXT: Considerable debate exists regarding the optimal surgical approach for adult spinal deformity (ASD). It remains unclear which approach, posterior-only or combined anterior-posterior (AP), is more cost-effective. Our goal is to determine the 2-year cost per quality-adjusted life year (QALY) for each approach. PURPOSE: To compare the 2-year cost-effectiveness of surgical treatment for ASD between the posterior-only approach and combined AP approach. STUDY DESIGN: Retrospective economic analysis of a prospective, multicenter database PATIENT SAMPLE: From a prospective, multicenter surgical database of ASD, patients undergoing five or more level fusions through a posterior-only or AP approach were identified and compared. METHODS: QALYs gained were determined using baseline, 1-year, and 2-year postoperative Short Form 6D. Cost was calculated from actual, direct hospital costs including any subsequent readmission or revision. Cost-effectiveness was determined using cost/QALY gained. RESULTS: The AP approach showed significantly higher index cost than the posterior-only approach ($84,329 vs. $64,281). This margin decreased at 2-year follow-up with total costs of $89,824 and $73,904, respectively. QALYs gained at 2 years were similar with 0.21 and 0.17 in the posterior-only and the AP approaches, respectively. The cost/QALY at 2 years after surgery was significantly higher in the AP approach ($525,080) than in the posterior-only approach ($351,086). CONCLUSIONS: We assessed 2-year cost-effectiveness for the surgical treatment through posterior-only and AP approaches. The posterior-only approach is less expensive both for the index surgery and at 2-year follow-up. The QALY gained at 2-years was similar between the two approaches. Thus, posterior-only approach was more cost-effective than the AP approach under our study parameters. However, both approaches were not cost-effective at 2-year follow-up.


Posted May 15th 2020

Successful Aging in East Asia: Comparison among China, Korea, and Japan.

Jinmyoung Cho, Ph.D.

Jinmyoung Cho, Ph.D.

Nakagawa, T., J. Cho and D. Yeung (2020). “Successful Aging in East Asia: Comparison among China, Korea, and Japan.” J Gerontol B Psychol Sci Soc Sci Apr 23. pii: gbaa042. [Epub ahead of print].

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OBJECTIVES: Heterogeneity in successful aging has been found across countries. Yet, comparable evidence is sparse except in North America and Europe. Extending prior research, this study examined the prevalence and correlates of successful aging in East Asian: China, Korea, and Japan. METHOD: We used harmonized datasets from national surveys. A total of 6,479 participants (aged between 65 and 75) were analyzed. Using Rowe and Kahn’s (1987, 1997) model, successful aging was defined as having no major diseases, no difficulty performing activities of daily living, obtaining a median or higher score on tests of cognitive function, and being actively engaged. RESULTS: The average prevalence of successful agers was 17.6%. There were variations in the global and specific measures of successful aging within and across countries, even after controlling for individual sociodemographic factors (age, gender, and education). The odds of aging successfully was highest in Japan and lowest in China, especially in the rural areas. Being younger and males were associated with a higher likelihood of successful agers in both global and specific measures. DISCUSSION: This study observed heterogeneity in successful aging in East Asia. To identify policy implications, future research should explore potential societal factors influencing individuals’ opportunities for successful aging.


Posted May 15th 2020

SMARCB1 Gene Mutation Predisposes to Earlier Development of Glioblastoma: A Case Report of Familial GBM.

Ekokobe Fonkem, D.O.

Ekokobe Fonkem, D.O.

Mukherjee, S., E. Stroberg, F. Wang, L. Morales, Y. Shan, A. Rao, J. H. Huang, E. Wu and E. Fonkem (2020). “SMARCB1 Gene Mutation Predisposes to Earlier Development of Glioblastoma: A Case Report of Familial GBM.” J Neuropathol Exp Neurol 79(5): 562-565.

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Glioblastoma (GBM) is the most aggressive adult brain tumor. While GBM typically occurs sporadically, familial GBM can be associated with certain hereditary disorders and isolated familial GBMs in the absence of syndrome are rare. Relevant hereditary factors have remained elusive in these cases. Understanding specific genetic abnormality may potentially lead to better treatment strategies in these patients. Here, we analyzed GBM tissue from our patient and 2 afflicted family members, with next generation sequencing to better understand the genetic alterations associated with this disease development. DNA was extracted and sequenced and the data were then analyzed. Results revealed 2 common mutations in afflicted family members; PDGFRA and HRAS. In addition, both siblings showed a mutation of the SMARCB1 gene. The sister of our patient exhibited a homozygous mutation, while our patient had heterozygous mutation of this gene in the tumor tissue. This result suggests that mutation of SMARCB1, either alone or in the presence of PDGFRA and HRAS mutations, is associated with earlier onset GBM.