Risk of hyperglycemia attributable to everolimus in cancer patients: A meta-analysis

Xu, Kevin Y; Shameem, Raji; Wu, Shenhong

doi:10.3109/0284186x.2016.1168939

Cited by 22 publications

(16 citation statements)

References 26 publications

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“…The Jadad scoring system allocated points based on the declaration of randomization, appropriate method of randomization, description of double-blind trial design, appropriate double-blinding, and description of dropouts and withdrawals [13]. Our utilization of study quality and use of the Jadad scoring system is consistent with similarly designed meta-analyses in the literature [14,15].…”

Section: Study Selectionsupporting

confidence: 48%

Risk of Liver Toxicity with Nivolumab Immunotherapy in Cancer Patients

Zarrabi

Wu²

2018

Oncology

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Background: Nivolumab is approved for the treatment of many cancers. This meta-analysis was conducted to determine the risk of hepatotoxicity with nivolumab therapy. Methods: An analysis from all phase I–III clinical trials up to December 2016 examining nivolumab was conducted. Data on elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were extracted from the safety profiles of each trial. Incidence and relative risk (RR) were calculated using random- or fixed-effects models with 95% confidence intervals (CIs). Results: The incidences of all-grade and high-grade elevations in AST were 5.4% (95% CI 3.2–9.1) and 1.6% (95% CI 0.9–3.0), respectively. The incidences of all-grade and high-grade elevations in ALT were 4.9% (95% CI 2.9–8.2) and 1.7% (95% CI 0.9–3.1), respectively. Elevations of both laboratory markers were significantly increased when compared to control (p < 0.001). Nivolumab significantly increased the RR of AST/ALT elevations; RRs were 1.58 (95% CI 1.1–2.2) for all-grade AST elevation, and 1.62 (95% CI 1.2–2.3) for all-grade ALT elevation. Subgroup analysis of all-grade AST or ALT elevation revealed a significant variation among tumor types (p < 0.001) and with combination with ipilimumab (p < 0.001). Conclusions: Nivolumab is associated with significantly increased risk of liver toxicity.

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Section: Study Selectionsupporting

confidence: 48%

Risk of Liver Toxicity with Nivolumab Immunotherapy in Cancer Patients

Zarrabi

Wu²

2018

Oncology

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“…In these cases, the severity of the hyperglycemia, like any other side effect, is assigned a grade 1–4. In most cases, rapamycin/everolimus-associated hyperglycemia is grade 1–2 and does not lead to treatment interruption 73,74 .…”

Section: Rapamycin-induced Hyperglycemiamentioning

confidence: 99%

Fasting and rapamycin: diabetes versus benevolent glucose intolerance

Blagosklonny

2019

Cell Death Dis

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Rapamycin (Sirolimus) slows aging, extends life span, and prevents age-related diseases, including diabetic complications such as retinopathy. Puzzlingly, rapamycin can induce insulin sensitivity, but may also induce insulin resistance or glucose intolerance without insulin resistance. This mirrors the effect of fasting and very low calorie diets, which improve insulin sensitivity and reverse type 2 diabetes, but also can cause a form of glucose intolerance known as benevolent pseudo-diabetes. There is no indication that starvation (benevolent) pseudo-diabetes is detrimental. By contrast, it is associated with better health and life extension. In transplant patients, a weak association between rapamycin/everolimus use and hyperglycemia is mostly due to a drug interaction with calcineurin inhibitors. When it occurs in cancer patients, the hyperglycemia is mild and reversible. No hyperglycemic effects of rapamycin/everolimus have been detected in healthy people. For antiaging purposes, rapamycin/everolimus can be administrated intermittently (e.g., once a week) in combination with intermittent carbohydrate restriction, physical exercise, and metformin.

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“…According to meta-analyses including patients with NETs, treatment with everolimus as well as other mTOR inhibitors, is most commonly associated with an increased risk of stomatitis [150–153], rash[151,154], fatigue[155], infection[156], pulmonary toxicities [152,157,158], hyperglycemia[155,159], anemia[160,161], and thrombocytopenia[160]. The pharmacokinetic analysis of RADIANT-2 trial also revealed that an increased everolimus minimum concentration was associated with higher risk for pulmonary and metabolic events[64].…”

Section: Safety Of Everolimus (Table 6)mentioning

confidence: 99%

“…From this viewpoint, one possible strategy for treatment decision-making could be based on patient tolerance, comorbidities, and toxicity profiles. Specifically, everolimus is not indicated in patients with impaired pulmonary function, uncontrolled infections and metabolic disorders[152,155–159]. …”

Section: Expert Opinionmentioning

confidence: 99%

Everolimus in the treatment of neuroendocrine tumors: efficacy, side-effects, resistance, and factors affecting its place in the treatment sequence

Lee

Ito

Jensen

2018

Expert Opinion on Pharmacotherapy

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Introduction: Since the initial approval of everolimus in 2011, there have been a number of important changes in therapeutic/diagnostic modalities as well as classification/staging systems of neuroendocrine tumors (NETs), which can significantly impact the use of everolimus in patients with advanced NETs. Areas covered: The efficacy of everolimus monotherapy and combination therapy demonstrated in clinical studies involving patients with advanced NETs are reviewed. Several factors affecting everolimus’ use are described including: the development and routine use of NET classification/staging systems; widespread use of molecular imaging modalities; side-effects; drug resistance; and the availability of other treatment options. Furthermore, the current position of everolimus in the treatment approach is discussed, taking into account the recommendations from the recent guidelines. Expert opinion: Although everolimus demonstrated its high efficacy and tolerability in the RADIANT trials and other clinical studies, there still remain a number of controversies related to everolimus treatment in the management of NETs. The synergistic anti-growth effect of other agents in combination with everolimus or its effect on overall survival have not been established. The appropriate order of the use of everolimus in the treatment of advanced NETs still remains unclear, which needs to be defined in further studies and will be addressed in the new guidelines.

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Risk of hyperglycemia attributable to everolimus in cancer patients: A meta-analysis

Cited by 22 publications

References 26 publications

Risk of Liver Toxicity with Nivolumab Immunotherapy in Cancer Patients

Risk of Liver Toxicity with Nivolumab Immunotherapy in Cancer Patients

Fasting and rapamycin: diabetes versus benevolent glucose intolerance

Everolimus in the treatment of neuroendocrine tumors: efficacy, side-effects, resistance, and factors affecting its place in the treatment sequence

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