Adverse glycaemic effects of cancer therapy: indications for a rational approach to cancer patients with diabetes Marco Gallo, Giovanna Muscogiuri, Francesco Felicetti, Antongiulio Faggiano, Francesco Trimarchi, Emanuela Arvat, Riccardo Vigneri, Annamaria Colao PII: DOI: Reference:

S0026-0495(17)30265-2 doi: 10.1016/j.metabol.2017.09.013 YMETA 53653

To appear in:

Metabolism

Received date: Accepted date:

30 April 2017 19 September 2017

Please cite this article as: Gallo Marco, Muscogiuri Giovanna, Felicetti Francesco, Faggiano Antongiulio, Trimarchi Francesco, Arvat Emanuela, Vigneri Riccardo, Colao Annamaria, Adverse glycaemic effects of cancer therapy: indications for a rational approach to cancer patients with diabetes, Metabolism (2017), doi: 10.1016/j.metabol.2017.09.013

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ACCEPTED MANUSCRIPT Adverse glycaemic effects of cancer therapy: indications for a rational approach to cancer patients with diabetes

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Marco Gallo1, MD, Giovanna Muscogiuri2, MD, Francesco Felicetti3, MD, Antongiulio Faggiano4,

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MD, PhD, Francesco Trimarchi5, MD, PhD, Emanuela Arvat1 ,MD, PhD, Riccardo Vigneri6, MD,

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PhD, Annamaria Colao7, MD, PhD 1

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Oncological Endocrinology Unit, Department of Medical Sciences, University of Turin, AOU Città della Salute e della Scienza di Torino, Turin, Italy 2 Ios and Coleman Medicina Futura Medical Centre, Naples, Italy 3 Transition Unit for Childhood Cancer Survivors, Department of Oncology, AOU Cittá della Salute e della Scienza di Torino, Turin, Italy 4 Thyroid and Parathyroid Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione G. Pascale” – IRCCS, Naples, Italy 5 Accademia Peloritana dei Pericolanti at the University of Messina, Messina, Italy. 6 Endocrinology, University of Catania, Garibaldi-Nesima Medical Center, Catania, Italy 7 Department of Clinical Medicine and Surgery, University "Federico II", Naples, Italy

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Corresponding Author:

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Marco Gallo, MD Oncological Endocrinology Unit Department of Medical Sciences AOU Città della Salute e della Scienza – Molinette Via Genova 3, 10126 Turin, Italy Tel.: +39.011.6334528; Fax: +39.011.6334703 email: [email protected] Word Count: 5140

Number of Figures: 1 Number of Tables: 4 Acknowledgments This review has been funded by the ‘NIKE’ project (Neuroendocrine tumors Innovation Knowledge and Education) led by Prof Annamaria Colao, which aims at increasing the knowledge on neuroendocrine tumours.

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ACCEPTED MANUSCRIPT Abstract Diabetes and cancer are common, chronic, and potentially fatal diseases that frequently co-exist. Observational studies have reported an increased risk of cancer in patients with diabetes.

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Furthermore, many patients with cancer already have diabetes, or develop hyperglycemia as a

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consequence of the tumor or of cancer therapies, and coexisting diabetes confers a greater risk of mortality for many malignancies. Managing oncologic patients with diabetes is often complicated,

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since the co-existence of diabetes and cancer poses several complex clinical questions: what level of glycemic control to achieve, which therapy to use, how to deal with glucocorticoid therapies and artificial nutrition, how diabetes complications can affect cancer management, which drug-

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drug interactions should be taken into account, or even how to manage diabetes at the end of life. In the clinical setting, both at hospital and at home, there are little agreed, evidence-based guidelines on the best management and criteria upon which clinical decisions should be based. A practical solution lies in the implementation of care networks based on communication and

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ongoing collaboration between Oncologists, Endocrinologists, and the nursing staff, with the patient at the center of the care process. This manuscript aims to review the current evidence on

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the effect of cancer therapies on glucose metabolism and to address some of the more common

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challenges of diabetes treatment in patients with cancer.

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Keywords: Diabetes, cancer, cancer therapy, diabetes therapy, clinical management

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ACCEPTED MANUSCRIPT Introduction Diabetes mellitus (DM) has been clearly identified as a significant and independent risk factor for both incidence and mortality of more common cancers. Various types of cancer, including breast,

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liver, pancreas, colorectum, bladder, endometrium, and non-Hodgkin lymphoma, are more

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frequent in patients with diabetes, with a relative risk ranging from 1.1 to 2.5 [1-9]. Hepatocellular carcinoma has the strongest association with DM (relative risk 2.5)[2].

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Both type 1 and type 2 DM are associated with an increased risk of developing cancer, although they differ for both metabolic and hormonal characteristics. Hyperinsulinemia due to insulinresistance is a recognized link between the increased cancer risk and type 2 DM [10-11]

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Hyperinsulinemia also occurs in type 1 DM, characterized by an absolute deficiency of endogenous insulin secretion. In these patients subcutaneous (s.c.) injected exogenous insulin, skipping the portal system and the liver, causes peripheral hyperinsulinemia (and hepatic hypoinsulinemia). However, because of differences in pathophysiology, patient age, and disease duration, type 1 DM

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patients have a different pattern of cancer risk relative to type 2 DM patients [12-13]. Moreover, additional factors, more prevalent in type 1 DM (i.e. nulliparity, fertility disorders, Helicobacter

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pylori infection, pernicious anaemia), may favour site-specific tumours in these patients, such as endometrial and gastric cancer [14-17].

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Cancer mortality is also increased in patients with DM compared to non-people with DM. This association has been reported for both short-term and long-term mortality [18-21]. In addition to

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hyperglycaemia and hyperinsulinemia, that favour cancer progression and aggressiveness, many factors can contribute to the increased cancer-related mortality in DM. These patients often undergo less aggressive anticancer treatments for the concurrence of cardiac, renal, and neuropathic complications, which may in turn concur to the worse therapeutic response [18, 22]. A higher prevalence of infections, increased surgery and post-surgery mortality, and enhanced toxicity of therapies, have also been reported as additional causes of worse outcome in patients with cancer and DM [23-27]. Coexisting DM, therefore, increases both overall and specific mortality in patients with cancer [18, 20, 23]. Estimates suggest that 8-18% of cancer patients have co-existent DM [29-31]. As a consequence, managing cancer patients with DM is a common and also complicated situation, due to the heterogeneity of the two diseases and the general condition of the individual patient. It should also be considered that the presence of DM is not known in a considerable number of patients, 3

ACCEPTED MANUSCRIPT and sometimes hyperglycaemia is newly detected both when already present before the cancer diagnosis and also when caused or aggravated by the tumour.

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Patients with long-lasting and poorly-controlled DM present a peculiar challenge to oncologists

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since the frequent presence of renal, cardiac, or neuropathic complications can be worsened by some chemotherapeutic agents. Therefore, the patients’ clinical condition might induce to reduce the dose and/or modify the timing of chemotherapy, potentially at the expense of a reduced

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effectiveness [22, 32]. In any case, patients with DM should be carefully evaluated before starting

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chemotherapy and side-effects of treatment should be monitored [33]. Hyperglycaemia and DM management, therefore, are crucial to avoid the deleterious effects of the combined cancer/diabetes condition that will negatively affect quality of life and overall survival in these patients. To determine the appropriate glycaemic target and the optimal combined treatment for both diabetes and cancer is a difficult task, and a personalized approach is

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required in these patients. However, for both the hospital clinical setting and outpatients, there is limited published evidence on the criteria to direct clinical decisions for the best management of

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the diseases.

This manuscript aims to describe the (early and late) consequences of cancer therapies on glucose

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with cancer.

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metabolism, and to address some of the more common challenges of DM treatments in patients

Search strategy and selection criteria Each scientific expert supplied a first draft manuscript on a specific aspect of the review’s topic. Articles were individually retrieved by each author up until April 2017, by search in PubMed (MEDLINE), EMBASE, and Cochrane Library using at least one of the following terms: type 2 diabetes, cancer, cancer treatment, antidiabetic drugs, insulin resistance, insulin secretion supplemented by references included in the retrieved articles, meta-analyses, and reviews. Studies were excluded if they were not in English. All manuscripts were then exchanged and discussed among all authors by e-mail. Each statement was subjected to voting by all authors as “yes” (agreement with the content and/or wording) or “no” (disagreement). Adopted rule was that statements supported by ≥75 % of votes would be immediately accepted, while those with 36 Gy) para-aortic nodes/spleen irradiation, whereas lower doses had no

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effect on the risk [77]. In CSs who underwent both autologous and allogenic hematopoietic stem cells transplantation (HCT) the risk of DM increased 2.0-3.6 folds when compared to sibling donors

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[78]. Within two years post-HCT the incidence of DM was 30% in allogenic HCT recipients (both adult and paediatric patients), being the exposure to high-dose corticosteroids (cumulative prednisone dose > 0.25 mg/kg/day) a risk factor for persistent DM [79]. An increased risk of

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abnormal glucose tolerance and reduced insulin sensitivity (with a reduced subcutaneous and increased visceral fat distribution, increased total fat mass, and reduced lean mass) were reported in acute lymphoblastic leukaemia survivors treated with HCT and total body irradiation, compared to patients treated only with chemotherapy [80]. The risk of developing DM in the first year post-

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diagnosis was 53% higher in colorectal CSs than in controls, and remained 19% higher in the fifth year post-diagnosis [81]. A modest increase in the incidence of DM was also reported in a wide

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cohort of postmenopausal breast cancer survivors, with the highest risk found in the first 2 years after cancer diagnosis for patients who had received adjuvant therapy [82].

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According to the mounting evidence and recommendations proposed by international cancer survivorship institutions [83-85], CSs - especially those at high risk of DM - should be periodically

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evaluated by oncologists, general practitioners, or long-term physicians, and enrolled in screening programs for early detection of glucose metabolism abnormalities. Moreover, when a patient is referred to the endocrinologist/diabetologist for the first time, previous cancer diagnoses and anticancer treatments in the past medical history should be carefully taken into account. Indeed, in these patients, management of DM should be considered as part of a multidisciplinary approach to the late effects of anticancer treatments (managing the CV risk and prevention or early detection of a second neoplasm). In childhood CSs, the Children’s Oncology Group recommends checking every 2 years (or more frequently if indicated by individual characteristics) fasting blood glucose (or glycated haemoglobin [HbA1c] levels) and/or lipid profile in patients at risk of impaired glucose metabolism and/or dyslipidaemia [84]. Moreover, endocrine disorders (such as hypothyroidism, hypogonadism, and growth hormone [GH] deficiency) may frequently occur in childhood CSs [86] and deserve attention due to their potential metabolic consequences.

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ACCEPTED MANUSCRIPT Indications for the treatment of hyperglycaemia/diabetes in cancer patients a. Glycaemic targets

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When managing DM in cancer patients many issues that complicate the therapeutic approach

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should be considered. Among them the most relevant are the type of DM, the patient's actual position in the trajectory of his/her oncologic condition and life expectancy , the need of

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corticosteroids and other drugs with known detrimental effects on metabolism, the presence of nutritional problems (e.g., anorexia, nausea, or vomiting), liver and renal function [22, 87-88].

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Patients with already known or with undiagnosed prediabetes, insulin resistance, and familiarity for diabetes are, of course, at higher risk and should be more actively monitored. Considering the prevalence of these metabolic abnormalities, a HbA1c measurement before starting anti-cancer treatments known to affect glucose metabolism should be recommended in all cases.

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Observational studies suggest that poor glycaemic control is associated with a worse prognosis in patients with cancer [26, 89]. Furthermore, if not adequately managed, hyperglycaemia can

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negatively impact the patient nutritional condition, the performance status, and the quality of life,

disease control.

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all of which could lead to reductions in chemotherapy dosing and reduced chances of better

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Even if no randomized trial has been carried out to show that treating hyperglycaemia improves the outcome of cancer patients, a pragmatic approach for good metabolic control in such patients is widely suggested [90]. DM definitely increases the risk of cardiovascular events and susceptibility to infections, both frequent and relevant problems in patients with cancer. Clearly, the aggressiveness of glucose control should be related to life-expectancy, since the prevention of micro- and macrovascular complications is no longer an aim when life-expectancy is short (Figure 1). Several Patients with DM and cancer often meet the criteria for the definition of frailty (a clinical recognizable status of increased vulnerability meeting ≥3 out of five phenotypic criteria: unintentional weight loss, low physical activity, weakness, slow walking speed, and self-reported exhaustion) [91-92]. Anyway, for patients with a more limited life expectancy and with relevant

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ACCEPTED MANUSCRIPT comorbidities, a less stringent glycaemic target may better fit for the purpose (e.g., a HbA1c target of 7.6-8.5%)[93-94].

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HbA1c can be usefully employed as a screening test for pre-existing DM in cancer patients, but

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capillary glucose testing (fasting and post-prandial) may be necessary to recognize asymptomatic hypoglycaemia and acute hyperglycaemia spikes (as induced by glucocorticoids) that would not be detected by HbA1c measurement. Moreover, HbA1c accuracy may be reduced when significant

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anaemia or accelerated red cell turnover (due to the disease or to chemotherapeutic agents) are present. Therefore, in cancer patients with DM, glycaemic targets and consequent treatment may

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be better defined by blood glucose levels than by HbA1c [90]. b. Antidiabetic therapy in patients with cancer

Since metformin can interfere with cancer promoting signalling pathways, there is biological

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plausibility for a cancer preventive effect of this antidiabetic drug. Indeed, epidemiologic evidence and in vitro studies make metformin a very attractive candidate for cancer prevention in people with

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diabetes, obesity, and/or insulin resistance, expecially for breast, colorectal, and endometrial cancer

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prevention [95,96]. However, Phase III randomized trials with the aim of evaluate if metformin (in addition to standard adjuvant therapy) can modify disease-free survival of cancer patients are still

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ongoing. Therefore, it’s at least too early to propose the use of metformin to prevente cancer recurrences in cancer survivors, unless deemed useful for concurrent diabetes.

As far as cancer patients with diabetes are concerned, mild hyperglycaemia can be treated with noninsulin antidiabetic drugs, by taking into account the benefits and disadvantages of the different agents . For instance, the gastrointestinal side-effects of metformin, acarbose, and glucagon-like peptide-1 (GLP-1) receptor agonists; the risk of hypoglycaemia with sulfonylureas and meglitinides; the slow onset of action of thiazolidinediones and the generally modest efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors; the risk of volume depletion, euglycaemic diabetic ketoacidosis, and genitourinary infections with SGLT2 inhibitors should be considered in each 11

ACCEPTED MANUSCRIPT patient (Table 3 and Table 4). Results of several human observational studies and recent metaanalyses indicate that people with DM treated with metformin may experience a significant

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survival advantage compared with those untreated, or treated with different glucose-lowering

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medications [97-99].

According to these findings, metformin has been proposed as the drug of choice for the treatment

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of patients with concurrent type 2 DM and cancer, if no specific contraindication is present. To be remembered is the required metformin discontinuation when contrast medium is going to be used

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for diagnostic imaging, because of the risk of contrast-induced nephropathy and subsequent lactic acidosis.

Insulin therapy, however, is required for most patients on active anti-cancer therapy as well as for people with DM already on insulin therapy. In addition, non-insulin therapies have inadequate

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efficacy and flexibility in cases of severe and intermittent hyperglycaemia (as can occur with the use of glucocorticoids), also considering that carbohydrate limitation in the diet is often

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impractical when food choices are already limited.

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For type 1 DM patients, the usual insulin regimen can be maintained, but close liaison with the local diabetes team is essential. These patients should continue to use their long-acting basal

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insulin daily (even if not eating), but may need to intensify the insulin dose in case of intercurrent illness or to reduce the dose when weight loss occurs. In type 2 DM patients different insulin regimens can be adopted to match the insulin supply to the prevailing glucose trend, individual patient preferences, and the overall experience and capability of the patient (or the caregiver). In insulin-treated patients prandial short-acting insulin analogs can be safely administered immediately after meals when food intake is unpredictable due to nausea, vomiting, or inability to eat, whereas the use of insulin sliding scales is generally discouraged [88, 90]. When the administration of basal insulin at the same time every day is not possible or is impractical (e.g., due to caregiver unavailability), insulin degludec or glargine 300 U/mL will allow for a greater flexibility in the timing of dose administration. Insulin degludec can be either anticipated or postponed at greater intervals (between 8 and 40 hours) with no negative effect on glycaemic control, both in patients with type 1 or type 2 DM [100-101] and Glargine 300 12

ACCEPTED MANUSCRIPT U/mL has a time administration flexibility up to 3 hours before or after the usual injection time [102].

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As regards antidiabetic drug doses, many aspects should be taken into account (eg, glycaemic

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target, clinical condition, tolerabilty, risk of adverse effects, drug-drug interactions). Therefore a personalized approach, which is a cornerstone of current diabetes treatment, is particularly

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important in this peculiar setting.

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c. Corticosteroids and diabetes management in cancer patients

Corticosteroids deserve a specific mention because patients with cancer are frequently treated with glucocorticoids for symptom control (e.g., to reduce pain, nausea, oedema, and anorexia, or as a premedication for chemotherapy with moderate/severe emetogenic potential), or as integral

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components of their cancer therapy (e.g., haematological malignancies). High dose steroids are associated with hyperglycaemia, both in people with DM and in patients with susceptibility to DM

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(i.e. prediabetes, insulin resistance, obesity, etc.) The effect of glucocorticoids in increasing glucose levels occurs mainly in the post-prandial phase with less effect on fasting glucose. For this

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reason, careful monitoring of post-prandial glucose levels is strongly recommended in all patients receiving steroids at high doses. In these patients measuring only fasting glucose can often result

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in under-diagnosis of hyperglycaemia, even severe [33]. Antidiabetic drugs mainly targeting postprandial hyperglycaemia may represent an alternative option to insulin, when hyperglycaemia is mild.

Nonetheless, despite the frequency of steroid-induced hyperglycaemia, prospective studies comparing the effectiveness of different antidiabetic therapies in these patients are lacking [90]. In this setting, insulin therapy is usually preferred because of its efficacy, flexibility, and safety. Indeed, the cyclical nature of chemotherapy associated with glucocorticoids frequently requires an intermittent intervention for the management of hyperglycaemia. A proactive approach to the management of steroid-induced hyperglycaemia may help to reduce the large glucose fluctuations in these patients [90] (Table 4).

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ACCEPTED MANUSCRIPT Major diabetes-related issues in cancer patients a. Drug–drug interactions

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Cancer patients with DM are at a significant risk of drug-drug interactions, since they are usually

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treated with multiple medications. Most oral antidiabetics are metabolised by the cytochrome P450 system (CYP), whose function can be impaired by cancer drugs, antifungals, and antibiotics

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[33]. Also TKIs are extensively metabolized by CYP. Combination therapies with drugs that are inhibitors or inducers of CYP, therefore, may affect both the antidiabetic and the anticancer drug

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concentration [103-104]. For instance, in people with DM chronically treated for myeloid leukemia, administration of imatinib and its derivatives may increase the tissue exposure to glibenclamide, glitazones, and meglitinides [103]. Moreover, several TKIs which are often prescribed for prolonged periods can enhance oral antidiabetic exposure (exp. with glibenclamide, meglitinides, and TZDs), while some antidiabetics can enhance or reduce intracellular exposure to

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TKIs [103-104]. DPP-4 inhibitors have been associated to an increased risk of incidence of nasopharyngitis, upper respiratory tract infections, urinary tract infections, and immune

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dysfunction. These adverse events could be due to the important role that DPP-4 plays in the immune system, as a T-cell co-stimulator, and to the T-cell activation of others DPP enzymes, such

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as DPP-8 and DPP-9, which could be off-target inhibited by DPP-4 inhibitors. To reduce the risk of these adverse events the use of highly selective DPP-4 inhibitors (e.g. alogliptin, linagliptin, and

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sitagliptin) can be considered [105]. Insulin, anyway, is always a safe alternative to these drugs. Furthermore, caution must be taken when prescribing fibrates and lipid-lowering agents in patients treated with anticancer agents targeting the PI3K-Akt-mTOR (PAM) pathway, because of the risk of interaction with various PAM pathway inhibitors (especially in the presence of liver damage) [106]. Finally, combination therapy of simvastatin or lovastatin with everolimus is potentially harmful and should be avoided. Other statins (rosuvastatin, atorvastatin, fluvastatin, or pravastatin) at the lowest efficacious dosage or other hypolipemic agents should be considered, when necessary [107]. b. Management of chronic diabetes complications Diabetes chronic complications (micro- and macro-vascular) are a major concern for people with DM. Regarding their prevention and treatment in cancer patients, there are no specific 14

ACCEPTED MANUSCRIPT recommendations. Nevertheless, the individual risk should be carefully assessed in patients receiving anti-cancer treatments that could induce or worsen hyperlipidemia and/or hypertension, like those targeting the PAM pathway [33, 106]. Antihypertensive drugs, statins, anti-aggregants,

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or even anticoagulants should be considered in these patients on the basis of the severity of

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metabolic abnormalities, of established chronic complications, and of life expectancy. Due to the increased susceptibility of patients with DM and cancer to infectious diseases, immunization with

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anti-pneumococcal and influenza vaccines is generally recommended. Furthermore, DM should be considered an additional risk factor when evaluating the indication for primary prophylaxis of

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febrile neutropenia from cytotoxic chemotherapy [33]. c. Artificial nutrition

Artificial (enteral or parenteral) nutrition is sometimes necessary for cancer patients with diabetes who are malnourished and unable to ingest adequate nutrients for a prolonged period of time.

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This treatment represents a further challenge to the management of oncologic patients with DM, potentially leading to acute exacerbations of hyperglycaemia. Once again, there is little published

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evidence to assist with deciding the best approach to hyperglycaemia in this particular setting [33, 90]. Diabetes-specific formulas often allow to maintain a satisfactory nutritional status, and insulin

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therapy (e.g., subcutaneous basal insulin and rapid/short-acting insulin s.c. or intravenous) is unavoidably the best option (Table 4).

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d. Diabetes management at the end-of-life End-of-life care should provide both physical and psychological support to help patients to die with dignity and with as less pain and symptoms as possible. Moreover, support should be provided for relatives and caregivers until the end. Glycaemic control goals become less stringent during end of life care, even if they should not be completely ignored to avoid symptomatic hypoglycaemia (e.g. sweating, tremor, anxiety, palpitations) and/or hyperglycaemia (e.g., polyuria, thirst, dehydration, drowsiness, blurred vision), which can impair the residual quality of life in these patients. Once again, there has been little formal research on the best clinical practice for cancer patients with DM who are dying, and available recommendations are based on expert opinions, surveys, and retrospective studies [30, 108-109]. As cancer disease progresses and prognosis worsens, drugs used to prevent vascular 15

ACCEPTED MANUSCRIPT complications (such as statins, anti-aggregants, and anti-hypertensives) should be discontinued or reduced [110]. When the estimated prognosis is months, blood glucose targets should be relaxed, and aimed at maintaining blood sugars within an acceptable range with minimal monitoring. To

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this end, recently published clinical care recommendations [111-112] suggest a glucose range of 6-

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15 mmol/L (110-270 mg/dL). In the terminal phase (prognosis of weeks or days) the only aims are to avoid hypoglycaemia and/or severe hyperglycaemia, and a more relaxed approach (10-20

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mmol/L; 180-360 mg/dL) seems more practical and equally sensible [30, 108]. The fact that symptoms related to severely altered blood sugar levels could be difficult to recognise, particularly for patients who are treated with opiates, should be taken into consideration. When the patient

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has entered the terminal phase, blood glucose monitoring should be reduced or avoided [111], and the burden of treatment minimised (to this end, once daily long-acting insulin is the simplest option). In any case, all decisions should be shared with and empathetically explained to the patient/relatives, and data about symptoms, quality of life, and general satisfaction, as well as (or

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as an alternative to) simple blood glucose monitoring should be gathered and recorded [113]. The observations mentioned above are mostly in agreement with the guidelines for DM

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management in older patients recently published by the American Diabetes Association [114].

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e. Educational issues for diabetes management in cancer patients As with any insulin-treated patient, comprehensive education about self-monitoring blood

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glucose, insulin storage and administration procedure (including devices and cartridges) , and the avoidance of/response to hypoglycaemias are critically important when managing patients with DM and cancer [88], especially when diabetes is newly diagnosed. Providing the patients and/or the caregivers with written information and educational videos can help, in our experience (e.g. see the tutorial video at https://www.youtube.com/watch?v=almiTiIcpbw). In patients with hypoglycaemia and marked cachexia and/or liver disease, hypoglycaemia may be less responsive to glucagon because glycogen stores are depleted. Finally, a matter of the utmost importance is to inform relatives about the possible impact of cancer on DM control, and the rationale for the management approach chosen on the basis of the current situation.

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ACCEPTED MANUSCRIPT Both DM and cancer are increasingly common conditions. Therefore, more and more frequently clinicians are dealing with oncologic patients affected by DM. To achieve the best level of care, the cooperation and interaction between different specialist figures play a key role.

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Diabetologists and Oncologists should work in a coordinated way. A good partnership, matching

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different competences and needs, benefits both the healthcare professionals and the patients, that must be kept at the centre of the care process.

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A practical solution lies in the organization of local healthcare networks with the implementation of clinical pathways, based on communication and ongoing collaboration between Endocrinologists/Diabetologists, Oncologists (and Hemato-Oncologists), Nutritionists, Palliative

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Medicine specialists, and the nursing staff that is directly dealing with these patients in the different settings (both for inpatient and outpatient clinics) [109]. In fact, shared clinical pathways can represent an useful tool to overcome uneven local care and to share basic clinical practice, even among centres located far one from the others. The organization and implementation of this

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network may allow to share the best approach for each patient, ensuring to overcome a strictly sectorial organization and to reach both a reciprocal improvement and an integration of different

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professional know-hows. At the same time, it can meet the need to guarantee a similarly high standard of care and appropriateness in the management of these complex patients in the same

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Conclusions

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geographical area.

DM and cancer are increasingly common comorbidities, and managing oncologic patients with DM is often complicated. Yet, there are little agreed, evidence-based guidelines on the best management and the criteria and rationale upon which base clinical decisions. The strength of this manuscript is to provide clinical advices on the management of diabetes in cancer settings although there are several limitations in the studies performed on this topic that avoid to draw final conclusion. In fact most of the studies are retrospective and were not designed with the aim to investigate diabetic management in cancer patients as primary outcome. Further, several studies enrolled heterogeneous population in terms of oncologic therapy that could interfere with the action of antidiabetic drugs. The general consideration is that cancer patients with DM are more fragile subjects with a variety of different pathophysiological and clinical aspects of the two diseases, and the need of multiple drugs. A personalized approach that must consider multiple mechanisms and interactions is therefore required. 17

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Figure 1. Setting a glycaemic target in oncologic patients with diabetes

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As suggested by the ADA/EASD Position Statement [88], many elements should be considered

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during the decision-making process to determine how intense should be the efforts to achieve glycaemic targets. In an oncologic patient with diabetes, four domains are particularly relevant:

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life-expectancy, risk of drug side effects, significant comorbidities, and support systems. Occasionally, HbA1c may be misleading in this setting, whereas self-monitoring of blood glucose

with the patient and/or the caregivers.

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(SMBG) may be more useful. Decision-making about glycaemic targets should always be shared

CAD, coronary artery disease; CHD, congestive heart failure; SMBG, self-monitoring of blood

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glucose

Author contributions

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MG, GM, and RV wrote this manuscript and provided the critical revision of the article. FF and AF contributed to draft the manuscript. AC, EA, FT, and RV contributed to the conception and design

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of the work. AC provided the final approval of the version to be submitted. Funding

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This review has been funded by the ‘NIKE’ project (Neuroendocrine tumors Innovation Knowledge and Education) led by Prof Annamaria Colao, which aims at increasing the knowledge on neuroendocrine tumours. Conflict of Interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors.

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ACCEPTED MANUSCRIPT References 1. Larsson SC, Mantzoros CS, Wolk A. Diabetes mellitus and risk of breast cancer: a meta-analysis. Int J Cancer 2007;121(4):856–862.

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2. El-Serag EB, Hampel H, Javadi F. The association between diabetes and hepatocellular

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carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol 2006;4(3):369–380.

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3. Huxley R, Ansary-Moghaddam A, Berrington de Gonzalez A, Barzi F, Woodward M. Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies. Br J Cancer 2005; 92(11):2076– 2083.

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4. Larsson SC, Orsini N, Wolk A. Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J Natl Cancer Inst 2005;97(22):1679–1687.

5. Larsson SC, Orsini N, Brismar K, WolkA. Diabetes mellitus and risk of bladder cancer: a metaanalysis. Diabetologia 2006;49(12):2819–2823.

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6. Friberg E, Orsini N, Mantzoros CS, Wolk A. Diabetes mellitus and risk of endometrial cancer: a meta-analysis. Diabetologia 2007;50(7):1365–1374.

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7. Mitri J, Castillo J, Pittas AG. Diabetes and risk of Non-Hodgkin’s lymphoma: meta-analysis of observational studies. Diabetes Care 2008;31(12):2391–2397.

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8. Bansal D, Bhansali A, Kapil G, Undela K, Tiwari P. Type 2 diabetes and risk of prostate cancer: a meta-analysis of observational studies. Prostate Cancer Prostatic Dis 2013;16(2):151–158.

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9. Shin HY, Jung KJ, Linton JA, Jee SE. Association between fasting serum glucose levels and incidence of colorectal cancer in Korean men: the Korean Cancer Prevention Study-II. Metabolism 2014;63(10):1250-1256.

10. Sciacca L, Vigneri R, Tumminia A, Frasca F, Squatrito S, Frittitta L et al. Clinical and molecular mechanisms favoring cancer initiation and progression in diabetic patients. Nutr Metab Cardiovasc Dis 2013;23(9):808-815. 11. Mendonça FM, de Sousa FR, Barbosa AL, Martins SC, Araújo RL, Soares R et al. Metabolic syndrome and risk of cancer: which link? Metabolism 2015;64(2):182-189. 12. Zendehdel K, Nyrén O, Ostenson CG, Adami HO, Ekbom A, Ye W. Cancer incidence in patients with type 1 diabetes mellitus: a population-based cohort study in Sweden. J Natl Cancer Inst 2003;95(23):1797-1800.

19

ACCEPTED MANUSCRIPT 13. Carstensen B, Read SH, Friis S, Sund R, Keskimäki I, Svensson AM et al. Cancer incidence in persons with type 1 diabetes: a five-country study of 9,000 cancers in type 1 diabetic individuals. Diabetologia 2016;59(5):980-988.

T

14. Yeshaya A, Orvieto R, Dicker D, Karp M, Ben-Rafael Z. Menstrual characteristics of women

RI P

suffering from insulin-dependent diabetes mellitus. Int J Fertil Menopausal Stud 1995;40(5):269273.

SC

15. Parazzini F, Negri E, La Vecchia C, Benzi G, Chiaffarino F, Polatti A et al. Role of reproductive factors on the risk of endometrial cancer. Int J Cancer 1998; 76(6):784-786. 16. Oldenburg B, Diepersloot RJ, Hoekstra JB. High seroprevalence of Helicobacter pylori in

MA NU

diabetes mellitus patients. Dig Dis Sci 1996;41(3):458-461.

17. De Block CE, De Leeuw IH, Van Gaal LF. High prevalence of manifestations of gastric autoimmunity in parietal cell antibody-positive type 1 (insulin-dependent) diabetic patients. The Belgian Diabetes Registry. J Clin Endocrinol Metab 1999;84(11):4062-4067.

ED

18. Barone BB, Yeh HC, Snyder CF, Peairs KS, Stein KB, Derr RL et al. Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis. J Am

PT

Med Assoc 2008;300(23):2754–2764.

19. Huang Y, Cai X, Qiu M, Chen P, Tang H, Hu Y et al. Prediabetes and the risk of cancer: a meta-

CE

analysis. Diabetologia 2014;57(11):2261–2269. 20. Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA et al. Diabetes

AC

and cancer: a consensus report. CA Cancer J Clin 2010;60(4);207-221. 21. Zhou XH, Qiao Q, Zethelius B, Pyörälä K, Söderberg S, Pajak et al. DECODE Study Group, Diabetes, prediabetes and cancer mortality. Diabetologia 2010;53(9):1867–1876. 22. Psarakis HM. Clinical challenges in caring for patients with diabetes and cancer. Diabetes Spectrum 2006;19(3):157–162. 23. Ranc K, Jørgensen ME, Friis S, Carstensen B. Mortality after cancer among patients with diabetes mellitus: effect of diabetes duration and treatment. Diabetologia 2014;57(5): 927-934. 24. Barone BB, Yeh HC, Snyder CF, Peairs KS, Stein KB, Derr RL et al. Postoperative mortality in cancer patients with preexisting diabetes: systematic review and meta-analysis. Diabetes Care 2010;33(4):931–939. 25. Ferraro F, Lymperi S, Méndez-Ferrer S, Saez B, Spencer JA, Yeap BY et al. Diabetes impairs hematopoietic stem cell mobilization by altering niche function. Sci Transl Med 2011;3(104):104ra101. 20

ACCEPTED MANUSCRIPT 26. Weiser MA, Cabanillas ME, Konopleva M, Thomas DA, Pierce SA, Escalante CP et al. Relation between the duration of remission and hyperglycemia during induction chemotherapy for acute lymphocytic leukemia with a hyperfractionated cyclophosphamide, vincristine, doxorubicin, and

RI P

T

dexamethasone/methotrexate-cytarabine regimen. Cancer 2004;100(6):1179-1185. 27. Handelsman Y, Leroith D, Bloomgarden ZT, Dagogo-Jack S, Einhorn D, Garber AJ, Grunberger G et al. Diabetes and cancer: an AACE/ACE consensus statement. Endocr Pract 2013;19(4):675-693.

SC

28. Fedeli U, Zoppini G, Gennaro N, Saugo M. Diabetes and cancer mortality: a multifaceted association. Diabetes Res Clin Pract 2014;106:e86–e89.

MA NU

29. Ko C, Chaudhry S. The need for a multidisciplinary approach to cancer care. J Surg Res 2002;105:53–57.

30. McCoubrie R, Jeffrey D, Paton C, Dawes L. Managing diabetes mellitus in patients with

ED

advanced cancer: a case note audit and guidelines. Eur J Cancer Care 2015;14:244–248. 31. Habib SL, Rojna M. Diabetes and risk of cancer. ISRN Oncol 2013;ID 583786 doi: 10.1155/2013/583786.

PT

32. Klil-Drori AJ, Azoulay L, Pollak MN. Cancer, obesity, diabetes, and antidiabetic drugs: is the fog

CE

clearing? Nat Rev Clin Oncol 2017;14(2):85-99. 33. Mateo J, Castro F, Olmos D, on behalf of the European Society for Medical Oncology. Cancer

AC

treatment in patients with diabetes. In 2013 ESMO Handbook on Cancer Treatment in Special Clinical Situations: Edit. ESMO Press; 2013, p- 72-88. 34. Joshi S, Liu M, Turner N. Diabetes and its link with cancer: providing the fuel and spark to launch an aggressive growth regime. Biomed Res Int 2015;ID 390863. doi: 10.1155/2015/390863. 35. Zoller H, Tilg H. Nonalcoholic fatty liver disease and hepatocellular carcinoma. Metabolism 2016;65(8):1151-1160. 36. Warburg O. On the origin of cancer cells. Science 1956;123(3191):309-314. 37. Liu PP, Liao J, Tang ZJ, Wu WJ, Yang J, Zeng ZL et al. Metabolic regulation of cancer cell side population by glucose through activation of the Akt pathway. Cell Death Differ 2014;21(1):124135.

21

ACCEPTED MANUSCRIPT 38. Flores-López LA, Martínez-Hernández MG, Viedma-Rodríguez R, Díaz-Flores M, Baiza-Gutman LA. High glucose and insulin enhance uPA expression, ROS formation and invasiveness in breast cancer-derived cells. Cell Oncol (Dordr) 2016;39(4):365-378.

T

39. Mikawa T, LLeonart ME, Takaori-Kondo A, Inagaki N, Yokode M, Kondoh H. Dysregulated

RI P

glycolysis as an oncogenic event. Cell Mol Life Sci 2015;72(10):1881-1892.

40. Shafaee A, Dastyar DZ, Islamian JP, Hatamian M. Inhibition of tumor energy pathways for

SC

targeted esophagus cancer therapy. Metabolism 2015;64(10):1193-1198.

41. Papa V, Pezzino V, Costantino A, Belfiore A, Giuffrida D, Frittitta L et al. Elevated insulin receptor content in human breast cancer. J Clin Invest 1990;86(5):1503-1510.

MA NU

42. Frasca F, Pandini G, Scalia P, Sciacca L, Mineo R, Costantino A et al. Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Mol Cell Biol 1999;19(5):3278-3288.

43. Belfiore A, Frasca F, Pandini G, Sciacca L, Vigneri R. Insulin receptor isoforms and insulin

ED

receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr Rev 2009;30(6):586-623.

PT

44. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003;348(17):1625-1638.

Dis 2006;16(1):1-7.

CE

45. Vigneri P, Frasca F, Sciacca L, Frittitta L, Vigneri R. Obesity and cancer. Nutr Metab Cardiovasc

AC

46. Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R. Diabetes and cancer. Endocr Relat Cancer 2009;16:1103-1123.

47. Dalamaga M, Diakopoulos KN, Mantzoros CS. The role of adiponectin in cancer: a review of current evidence. Endocr Rev. 2012;33(4):547-94. doi: 10.1210/er.2011-1015. 48. Dang CV, O'Donnell KA, Zeller KI, Nguyen T, Osthus RC, Li F. The c-Myc target gene network. Semin Cancer Biol 2006;16:253-264. 49. DeBerardinis RJ, Cheng T. Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 2010;29:313-324. 50. Shroff EH, Eberlin LS, Dang VM, Gouw AM, Gabay M, Adam SJ et al. MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism. Proc Natl Acad Sci USA 2015;112(21):6539-6544.

22

ACCEPTED MANUSCRIPT 51. Camarda R, Zhou AY, Kohnz RA, Balakrishnan S, Mahieu C, Anderton B et al. Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer. Nat Med 2016;22(4):427-432.

T

52. Flores-Calderón J, Exiga-Gonzaléz E, Morán-Villota S, Martín-Trejo J, Yamamoto-Nagano A.

RI P

Acute pancreatitis in children with acute lymphoblastic leukemia treated with L-asparaginase. J Pediatr Hematol Oncol 2009;31(10):790-793.

SC

53. Graber AL, Porte Jr D, Williams RH. Clinical use of diazoxide and studies of the mechanism of its hyperglycemic effects in man. Ann N Y Acad Sci 1968;150(2):303-308. 54. Faggiano A, Ferolla P, Grimaldi F, Campana D, Manzoni M, Davì MV et al. Natural history of

MA NU

gastro-entero-pancreatic and thoracic neuroendocrine tumors. Data from a large prospective and retrospective Italian epidemiological study: the NET management study. J Endocrinol Invest 2012;35(9):817-823.

55. González-Rodríguez E, Rodríguez-Abreu D, Spanish Group for Cancer Immuno-Biotherapy

Oncologist 2016;21(7):804-816.

ED

(GETICA). Immune Checkpoint Inhibitors: Review and Management of Endocrine Adverse Events.

PT

56. Hofmann L, Forschner A, Loquai C, Goldinger SM, Zimmer L, Ugurel S et al. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer

CE

2016;60:190-209.

57. Yamazaki N, Kiyohara Y, Uhara H, Fukushima S, Uchi H, Shibagaki N et al. Phase II study of

AC

ipilimumab monotherapy in Japanese patients with advanced melanoma. Cancer Chemother Pharmacol 2015;76(5):997-1004. 58. Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol 2012;13(5):459-465. 59. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016;375(19):18231833. 60. Nghiem PT, Bhatia S, Lipson EJ, Kudchadkar RR, Miller NJ, Annamalai L et al. PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma. N Engl J Med 2016;374(26):2542-2552. 61. Kaufman HL, Russell J, Hamid O, Bhatia S, Terheyden P, D'Angelo SP et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 2016;17(10):1374-1385. 23

ACCEPTED MANUSCRIPT 62. Weber J, Gibney G, Kudchadkar R, Yu B, Cheng P, Martinez AJ et al. Phase I/II Study of Metastatic Melanoma Patients Treated with Nivolumab Who Had Progressed after Ipilimumab. Cancer Immunol Res 2016;4(4):345-53.

T

63. Hwang JL, Weiss RE. Steroid-induced diabetes: a clinical and molecular approach to

RI P

understanding and treatment. Diabetes Metab Res Rev 2014;30(2):96-102.

64. Brady VJ, Grimes D, Armstrong T, Lo Biondo-Wood G. Management of steroid-induced

SC

hyperglycemia in hospitalized patients with cancer: a review. Oncol Nurs Forum 2014;41(6):E355E365.

65. Ariaans G, de Jong S, Gietema JA, Lefrandt JD, de Vries EG, Jalving M. Cancer-drug induced

MA NU

insulin resistance: innocent bystander or unusual suspect. Cancer Treat Rev 2015;41(4):376-384. 66. Mann M, Koller E, Murgo A, Malozowski S, Bacsanyi J, Leinung M. Glucocorticoidlike activity of megestrol. A summary of Food and Drug Administration experience and a review of the literature. Arch Intern Med 1997;157(15):1651-1656.

ED

67. Paplomata E, Zelnak A, O'Regan R. Everolimus: side effect profile and management of toxicities in breast cancer. Breast Cancer Res Treat 2013;140(3):453-462.

Statistics

Review,

PT

68. Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Altekruse SF et al. SEER Cancer 1975-2013,

National

Cancer

Institute.

Bethesda,

MD,

CE

http://seer.cancer.gov/csr/1975_2013/, based on November 2015 SEER data submission, posted to the SEER web site, April 2016.

AC

69. Oeffinger KC, Mertens AC, Sklar CA, Kawashima T, Hudson MM, Meadows AT et al. Childhood Cancer Survivor Study. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 2006;355(15):1572–1582. 70. Kero AE, Järvelä LS, Arola M, Malila N, Madanat-Harjuoja LM, Matomäki J et al. Late mortality among 5-year survivors of early onset cancer: a population-based register study. Int J Cancer 2015;136(7):1655–1664. 71. Lipshultz SE, Adams MJ, Colan SD, Constine LS, Herman EH, Hsu DT et al. Long-term cardiovascular toxicity in children, adolescents, and young adults who receive cancer therapy: pathophysiology, course, monitoring, management, prevention, and research directions: a scientific statement from the American Heart Association. Circulation 2013;128(17):1927–1995. 72. de Haas EC, Oosting SF, Lefrandt JD, Wolffenbuttel BH, Sleijfer DT, Gietema JA. The metabolic syndrome in cancer survivors. Lancet Oncol 2010;11(2):193–203.

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ACCEPTED MANUSCRIPT 73. Felicetti F, D'Ascenzo F, Moretti C, Corrias A, Omedè P, Grosso Marra W et al. Prevalence of cardiovascular risk factors in long-term survivors of childhood cancer: 16 years follow up from a prospective registry. Eur J Prev Cardiol 2015;22:762–770.

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74. Green DM, Cox CL, Zhu L, Krull KR, Srivastava DK, Stovall M et al. Risk factors for obesity in

RI P

adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 2012;30:246–255.

SC

75. Armenian SH, Xu L, Ky B, Sun C, Farol LT, Pal SK et al. Cardiovascular Disease Among Survivors of Adult-Onset Cancer: A Community-Based Retrospective Cohort Study. J Clin Oncol 2016;34:1122-1130.

MA NU

76. Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman U, Brønnum D et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med 2013;368:987998.

77. van Nimwegen FA, Schaapveld M, Janus CP, Krol AD, Raemaekers JM, Kremer LC et al. Risk of

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diabetes mellitus in long-term survivors of Hodgkin lymphoma. J Clin Oncol 2014;32(29):32573263.

PT

78. Baker KS, Ness KK, Steinberger J, Carter A, Francisco L, Burns LJ et al. Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the

CE

bone marrow transplantation survivor study. Blood 2007;109(4):1765-1772. 79. Majhail NS, Challa TR, Mulrooney DA, Baker KS, Burns LJ. Hypertension and diabetes mellitus in

AC

adult and pediatric survivors of allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2009;15(9):1100-1107. 80. Wei C, Thyagiarajan MS, Hunt LP, Shield SP, Stevens MC, Crowne EC. Reduced insulin sensitivity in childhood survivors of haematopoietic stem cell transplantation is associated with lipodystropic and sarcopenic phenotypes. Pediatr Blood Cancer 2015;62:1992-1999. 81. Singh S, Earle CC, Bae SJ, Fischer HD, Yun L, Austin PC et al. Incidence of Diabetes in Colorectal Cancer Survivors. J Natl Cancer Inst 2016;108(6):djv402. 82. Lipscombe LL, Chan WW, Yun L, Austin PC, Anderson GM, Rochon PA. Incidence of diabetes among postmenopausal breast cancer survivors. Diabetologia 2013;56:476-483. 83. Lin MH, Wood JR, Mittelman SD, Freyer DR. Institutional adherence to cardiovascular risk factor screening guidelines for young survivors of acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2015;37(4):e253-257.

25

ACCEPTED MANUSCRIPT 84. The Children’s Oncology Group, Long-term follow-up guidelines for survivors of childhood, adolescent, and young adult. Version 4.0—October 2013. http://www.survivorshipguidelines.org; 2013. [accessed April 2017]

T

85. DeFilipp Z, Duarte RF, Snowden JA, Majhai NSl, Greenfield DM, Miranda JL et al. Metabolic

RI P

Syndrome and Cardiovascular Disease after Hematopoietic Cell Transplantation: Screening and Preventive Practice Recommendations from the CIBMTR and EBMT. Biol Blood Marrow Transplant

SC

2016;22(8):1493-1503.

86. Brignardello E, Felicetti F, Castiglione A, Chiabotto P, Corrias A, Fagioli F et al. Endocrine health conditions in adult survivors of childhood cancer: the need for specialized adult-focused follow-up

MA NU

clinics. Eur J Endocrinol 2014;168:465-472.

87. Poulson j. The management of diabetes in patients with advanced cancer. J Pain Symptom Manage 1997;13:339–346.

88. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M et al. Management of

ED

hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of

PT

Diabetes. Diabetes Care 2015;38:140–149.

89. Lee W, Yoon YS, Han HS, Cho JY, Choi Y, Jang JY et al. Prognostic relevance of preoperative

CE

diabetes mellitus and the degree of hyperglycemia on the outcomes of resected pancreatic ductal

AC

adenocarcinoma. J Surg Oncol 2016;113(2):203-208. 90. Jacob P, Chowdhury TA. Management of diabetes in patients with cancer. QJM 2015;108:443– 448.

91. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001;56:M146-156. 92. Xue QL. The frailty syndrome: definition and natural history. Clin Geriatr Med 2011;27:1-15. 93. American Diabetes Association. Standards of Medical Care in Diabetes-2017. Diabetes Care 2017; 40(Suppl 1):S48-S56. 94. Sinclair AJ, Paolisso G, Castro M, Bourdel-Marchasson I, Gadsby R, Rodriguez Mañas L. European Diabetes Working Party for Older People 2011 clinical guidelines for type 2 diabetes mellitus. Executive summary. Diabetes Metab 2011;37(Suppl 3):S27-S38.

26

ACCEPTED MANUSCRIPT 95. Heckman-Stoddard BM, DeCensi A, Sahasrabuddhe VV, Ford LG. Repurposing metformin for the prevention of cancer and cancer recurrence. Diabetologia. 2017. doi: 10.1007/s00125-0174372-6.

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96. Provinciali N, Lazzeroni M, Cazzaniga M, Gorlero F, Dunn BK, DeCensi A. Metformin: risk-

RI P

benefit profile with a focus on cancer. Expert Opin Drug Saf. 2015;14(10):1573-85. doi: 10.1517/14740338.2015.1084289.

SC

97. Yin M, Zhou J, Gorak EJ, Quddus F. Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: a systematic review and meta-analysis. Oncologist 2013;18(12):1248-1255.

MA NU

98. Pierotti MA, Berrino F, Gariboldi M, Melani C, Mogavero A, Negri T et al. Targeting metabolism for cancer treatment and prevention: metformin, an old drug with multi-faceted effects. Oncogene 2013;32(12):1475-1487.

99. Perez-Lopez FR, Pasupuleti V, Gianuzzi X, Palma-Ardiles G, Hernandez-Fernandez W,

ED

Hernandez AV. Systematic review and meta-analysis of the effect of metformin treatment on overall mortality rates in women with endometrial cancer and type 2 diabetes mellitus. Maturitas

PT

2017;101:6-11.

100. Mathieu C, Hollander P, Miranda-Palma B, Cooper J, Franek E, Russell-Jones D et al. Efficacy

CE

and safety of insulin degludec in a flexible dosing regimen vs insulin glargine in patients with type 1 diabetes (BEGIN: Flex T1): a 26-week randomized, treat-to-target trial with a 26-week extension.

AC

J Clin Endocrinol Metab 2013;98(3):1154-1162. 101. Meneghini L, Atkin SL, Gough SC, Raz I, Blonde L, Shestakova M et al. The efficacy and safety of insulin degludec given in variable once-daily dosing intervals compared with insulin glargine and insulin degludec dosed at the same time daily: a 26-week, randomized, open-label, parallel-group, treat-to-target trial in individuals with type 2 diabetes. Diabetes Care 2013;36(4):858-864. 102. Riddle MC, Bolli GB, Home PM, Bergenstal RM, Ziemen M, Muehlen-Bartmer I et al. Efficacy and Safety of Flexible Versus Fixed Dosing Intervals of Insulin Glargine 300 U/mL in People with Type 2 Diabetes. Diabetes Technol Ther 2016;18(4):252-257. 103. Haouala A, Widmer N, Duchosal MA, Montemurro M, Buclin T, Decosterd LA. Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood 2011;117:e75–87.

27

ACCEPTED MANUSCRIPT 104. Casadei Gardini A, Marisi G, Scarpi E, Scartozzi M, Faloppi L, Silvestris N et al. Effects of metformin on clinical outcome in diabetic patients with advanced HCC receiving sorafenib. Expert

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Opin Pharmacother 2015;16:2719–2525.

RI P

105. Capuano A, Sportiello L, Maiorino MI, Rossi F, Giugliano D, Esposito K. Dipeptidyl peptidase-4 inhibitors in type 2 diabetes therapy--focus on alogliptin. Drug Des Devel Ther 2013;7:989-1001.

SC

106. Busaidy NL, Farooki A, Dowlati A, Perentesis JP, Dancey JE, Doyle LA et al. Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt-mTOR pathway. J Clin

MA NU

Oncol 2012;30:2919–2928.

107. Wiggins BS, Saseen JJ, Page RL, Reed BN, Sneed K, Kostis JB et al. Recommendations for Management of Clinically Significant Drug-Drug Interactions With Statins and Select Agents Used in Patients With Cardiovascular Disease: A Scientific Statement From the American Heart

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Association. Circulation 2016;134(21):e468-e495.

108. Dionisio R, Giardini A, De Cata P, Pirali B, Rossi S, Negri EM et al. Diabetes Management in End

PT

of Life: A Preliminary Report Stemming From Clinical Experience. Am J Hosp Palliat Care

CE

2015;32:588–593.

109. Gallo M, Gentile L, Arvat E, Bertetto O, Clemente G. Diabetology and oncology meet in a

AC

network model: union is strength. Acta Diabetol 2016;53:515-524. 110. Holmes HM, Todd A. Evidence-based deprescribing of statins in patients with advanced illness. JAMA Intern Med 2015;175:701–702. 111. Pan Birmingham Cancer Network: Guideline for the Management of Diabetes Mellitus in Palliative Medicine. http://www.uhb.nhs.uk/Downloads/pdf/CancerPbDiabetesMellitus.pdf. [accessed April 2017] 112. Diabetes UK: End of Life Diabetes Care - Clinical Care Recommendations. http://www.diabetes.org.uk/upload/Position%20statements/End-of-life-care-Clinicalrecs111113.pdf. [accessed April 2017]

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ACCEPTED MANUSCRIPT 113. Lindskog M, Kärvestedt L, Fürst CJ. Glycaemic control in end-of-life care: fundamental or futile? Curr Opin Support Palliat Care 2014;8:378–382.

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ACCEPTED MANUSCRIPT Table 1: Cancer therapies inducing or worsening diabetes mellitus Agents reducing the insulin sensitivity

L-asparaginase

Glucocorticoids

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Agents interfering with insulin production / secretion

Diazoxide

Megestrol acetate

Immune checkpoint inhibitors cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) -ipilimumab

b) mTOR inhibitors (everolimus)

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Anti-programmed cell death ligand-1 (PD-L1) antibodies -atezolizumab -avelumab

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c)

Tyrosine-kinase inhibitors -IR/IGF1R inhibitors -PI3K/AKT inhibitors

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b) Anti-programmed cell death receptor-1 (PD-1) antibodies -nivolumab -pembrolizumab

a)

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a)

Targeted therapies

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Table 2. National Cancer Institute severity scale for hyperglycaemia utilized for adverse event reporting. Grade FG >ULN - 160 mg/dL (>ULN - 8.9 mmol/L) 1 FG >160 - 250 mg/dL (>8.9 - 13.9 mmol/L) 2 >250 - 500 mg/dL (>13.9 - 27.8 mmol/L); hospitalization indicated 3 >500 mg/dL (>27.8 mmol/L); life-threatening consequences 4 Death 5 Modified from: Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 (http://evs.nci.nih.gov/ftp1/CTCAE/About.html) FG: fasting glucose; ULN: upper limit of normal

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ACCEPTED MANUSCRIPT Table 3. Main advantages and drawbacks of antidiabetic drugs in the oncologic patient Drugs Metformin

Advantages Low cost, mild weight loss#

Drawbacks Nausea, anorexia, vomiting, abdominal pain

Sulphonylureas

Glibenclamide, Gliclazide, Glimepiride, Glipizide, Gliquidone Nateglinide, Repaglinide

Low acquisition cost, efficacy

Hypoglycemia, weight gain#

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Contrasting steroid-induced postprandial hyperglycemia

Low cost, contrasting steroid-induced insulin resistance, preventing atherosclerosis progression Contrasting steroid-induced postprandial hyperglycemia

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Acarbose, Miglitol, Voglibose

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Alpha glucosidase inhibitors

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Thiazolidinediones Pioglitazone, Rosiglitazone

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Class Biguanides

DPP-4 inhibitors

Alogliptin, Linagliptin, Saxagliptin, Sitagliptin, Vildagliptin

Well tolerated, weight neutral

GLP-1 receptor agonists

Albiglutide, Dulaglutide, Exenatide, Liraglutide, Lixisenatide

Convenient (albiglutide and dulaglutide once weekly), cardiovascular benefit (liraglutide), weight loss#

SGLT-2 inhibitors

Canagliflozin,

Convenient,

Contraindications Renal and liver failure; hypoxemic respiratory failure, sepsis. Attention when contrastenhanced image examinations are scheduled Renal and liver failure

Hypoglycemia; limited efficacy; frequency of taking medication Anemia, oedema, bone fractures; slow onset of action, limited efficacy

Renal and liver failure

Abdominal pain, flatulence, diarrhea; low efficacy

partial intestinal obstruction; attention when abdominal RT is scheduled Severe liver failure

Upper respiratory tract infections? Pancreatitis? Heart failure? Low potency, high cost Nausea, anorexia, vomiting, abdominal pain; pancreatitis? Injectable training requirements; high cost Volume

Heart and liver failure

Severe gastrointestinal disease, severe renal failure, previous pancreatitis

Patients at 33

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Universally effective; anabolic effect; contrasting steroid-induced postprandial hyperglycemia, dosing/timing flexibility Detemir, Universally Glargine, ILPS effective; anabolic effect; convenient

increased risk of volume depletion; renal failure (ineffective)

Injectable training requirements;

None

Injectable training requirements; High cost

None

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Aspart, Glulisine, Lispro

depletion, dehydration, ketoacidosis, genital mycotic infections; high cost Hypoglycemia, Injectable training requirements; patient/relatives reluctance, weight gain#

None

Degludec, Glargine U300

Universally effective; anabolic effect; convenient; flexible dosing intervals

PT

Very long-acting insulin analogs with flexible time intervals for injection

ED

Long-acting (Basal) insulin analogs

MA NU

SC

Short-acting insulin analogs

cardiovascular benefit (canagliflozin and empagliflozin), weight loss#

RI P

Dapagliflozin, Empagliflozin

AC

CE

#: weight gain may be an advantage for weight-losing cancer patients with diabetes. Conversely, weight loss may be a drawback in the same setting.

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ACCEPTED MANUSCRIPT Table 4. Diabetes management in cancer patients Setting Preferred antidiabetic therapy  Metformin Chronic management of type 2 diabetes  Acarbose

SC

RI P

Sulfonylureas Meglitinides GLP-1 receptor agonists Pioglitazone DPP-4 inhibitors SGLT2 inhibitors Insulin therapy

ED PT



AC

CE

Diabetes management during corticosteroids treatment

Diabetes management during artificial nutrition

 

Metformin and acarbose if there are gastrointestinal symptoms Sulfonylureas and meglitinides, if there is high risk of hypoglycaemia SGLT2 inhibitors, if there is high risk of developing volume depletion and genitourinary infections Glibenclamide, thiazolidinediones, and meglitinides, if patients take imatinib and its derivatives for myeloid leukaemia Glibenclamide, meglitinides, and thiazolidinediones, if patients take TKIs

T



MA NU

      

Not recommended antidiabetic therapy









Mild hyperglycaemia: drugs targeting postprandial hyperglycaemia (sulfonylureas, meglitinides, GLP-1 receptor agonists, DPP-4 inhibitors) Severe hyperglycaemia: insulin therapy Insulin therapy, i.e. subcutaneous basal insulin and rapid/shortacting insulin s.c. or intravenous

The treatment of diabetes in cancer patients should take into account several factors. All diabetic drugs such as metformin, acarbose, sulfonylureas, meglitinides, GLP-1 receptor agonists, thiazolidinediones, DPP-4 inhibitors, SGLT2 inhibitors, and insulin therapy can be used. However, metformin and acarbose should be avoided if patients have gastrointestinal symptoms while sulfonylureas and meglitinides should be avoided if there is high risk of hypoglycaemia. SGLT2 inhibitors are not recommended if there is high risk of developing volume depletion and genitourinary infections. Glibenclamide, thiazolidinediones, and meglitinides could interfere with imatinib and its derivatives while glibenclamide, meglitinides, and thiazolidinediones with TKIs. The corticosteroid treatment is often associated to postprandial hyperglycaemia. Thus, antidiabetic drugs targeting post-prandial hyperglycaemia are 35

ACCEPTED MANUSCRIPT

AC

CE

PT

ED

MA NU

SC

RI P

T

suggested if hyperglycaemia is mild, otherwise insulin therapy is the recommended therapy. The best antidiabetic approach during artificial nutrition is insulin therapy.

36