Minimise Glycaemic Risk During Cancer Therapy to Achieve Better Outcomes

Cancer, Diabetes, and Cancer Treatment Share a Complex Relationship, and New Guidance from the Joint British Diabetes Societies Lists Important Steps to Reduce Glycaemic Risks During Cancer Therapy. Professor Umesh Dashora and Colleagues Outline the Key Recommendations

Introduction

Rates of diabetes in cancer are increasing. About 20% of individuals with cancer have diabetes, and cancer is the leading cause of death in people with diabetes.^1,2 Each of the different types of diabetes pose clinical challenges (Box 1).

Diabetes is associated with a higher risk of cancer;³ this association is most robust for breast, colorectal and endometrial cancer,⁴ and for intrahepatic cholangiocarcinoma.⁵ However, many studies suffer from significant heterogeneity and are therefore unable to reach clear conclusions.^3,4 The link between diabetes and cancer risk may be due to diabetes per se, treatments for diabetes, or associated shared risk factors such as obesity.⁴ 

People with cancer are also at increased risk of developing new onset diabetes or hyperglycaemia, as well as a worsening of their control of pre-existing diabetes^6–8 (Box 2). In addition, cancer treatment often involves steroids and chemotherapy, both of which may affect the pancreas or cause insulin resistance. Therefore, a patient may develop diabetes, or existing diabetes may get worse.^7,8 Finally, some conditions are linked to both diabetes and cancer, making it difficult to ascertain a causative role for diabetes in cancer. Examples include obesity,⁴ advancing age, and some dietary patterns.⁹

A new guideline from the Joint British Diabetes Societies for Inpatient Care (JBDS-IP) on the management of glycaemic control in patients with cancer will help clinicians involved in the care of these patients to identify and manage newly diagnosed diabetes and deterioration in glucose control in people with pre-existing diabetes.¹⁰ This article outlines the key recommendations in the guideline, and how to implement them.

Risks Associated with Diabetes in Patients with Cancer

People who have both diabetes and cancer have a poor prognosis, with a higher risk of hospital admissions,²⁰ sepsis,²¹ and of developing infections²¹ (and, in people with prostate cancer, a higher risk of haematological and non-haematological toxicity).²² They may also experience a poorer response to cancer therapies (often as a result of chemotherapy dose reductions or medication stoppage due to hyperglycaemic side effects),^23–28 a higher resistance to chemotherapeutic agents due to hyperglycaemia,²⁹ and a higher risk of chemotherapy-induced neutropenia³⁰ and of cancer recurrence,^6,19,31–39 with lower rates of disease-free survival and overall survival.⁴⁰ In addition, poor adherence to glucose-lowering drugs,⁴¹ negative impact on self-management behaviour,⁴² poor glycaemic control⁴² and quality of life,²⁵ and worse patient-reported outcomes⁴³ have been noted.

Early intervention to improve glycaemic control is likely to be of benefit, with possible improvement in the tolerability of anticancer therapy;⁴⁴ however, high-quality evidence from randomised controlled trials is not yet available.

Diabetes and Anticancer Treatment

The exact mechanism of the development of diabetes and hyperglycaemia in people on anticancer treatment remains unknown, and is dependent upon the type of therapy used. However, it is likely to be due to either loss of immune tolerance, or autoimmune destruction of pancreatic beta cells and dysregulation of signalling pathways, leading to insulin resistance.^45,46

Different systemic anticancer therapy (SACT) modalities are associated with different risks of diabetes and hyperglycaemia, ranging from less than 1% with nivolumab to 67% with busulfan.¹⁰ Glucocorticoids are used in the treatment of many cancers, and can cause hyperglycaemia and diabetes in a dose-dependent fashion.¹⁹ In one meta-analysis, the incidence of steroid-induced hyperglycaemia or steroid-induced diabetes was found to be 32.3% and 18.6%, respectively.⁴⁷ Another study found that, of 12.8% of inpatients on glucocorticoids, only 20.5% had had their blood glucose measured at admission.⁴⁸ Standardised guidelines are available from the JBDS for early detection and management of diabetes due to steroid treatment.⁴⁹ 

Some people are at higher risk of developing hyperglycaemia when given glucocorticoids, especially in high doses,⁵⁰ and this may not resolve once glucocorticoids are withdrawn. Risk factors for glucocorticoid-induced diabetes include:

• pre-existing type 1 or type 2 diabetes
• family history of diabetes
• obesity
• increasing age
• ethnic minorities
• impaired fasting glucose or impaired glucose tolerance (HbA_1c 42–47 mmol/mol)
• polycystic ovarian syndrome
• previous gestational diabetes
• previous development of hyperglycaemia on glucocorticoid therapy
• concurrent cytotoxic therapy known to cause hyperglycaemia.¹⁰

Diabetes and hyperglycaemia are both important complications for SACT and glucocorticoid treatment. This is not as well recognised as it should be in healthcare settings. Very often, the glycaemic complications of such therapies are complex, and require clear guidelines and multidisciplinary working.¹⁷

Diagnosing Impaired Glucose Tolerance, Diabetes, and Diabetic Emergencies 

Tables 1, 2, and 3 outline the diagnostic criteria for diabetes and impaired glucose tolerance, the identification of diabetic emergencies, and the symptoms of hyper- and hypo-glycaemia. For details on the management of diabetic emergencies, the JBDS has produced guidance on hyperosmolar hyperglycaemic state (HHS),⁵¹ diabetic ketoacidosis (DKA),⁵² and hypoglycaemia.⁵³  

Table 1: Diagnostic Criteria for Diabetes and Impaired Glucose Tolerance^10,54 

Table 2: How to Identify Diabetic Emergencies¹⁰

Box 3: Symptoms of Hyperglycaemia and Hypoglycaemia¹⁰ 

Steps to be Taken When Initiating Anticancer Treatment 

The following steps should to be taken when anticancer treatment of any type is started, whether a patient has a history of diabetes or not:¹⁰

• inform the patient’s GP about individuals at higher risk of hyperglycaemia (Tables 1 and 2) and ensure people have a capillary blood glucose (CBG) meter
• inform and educate people about the risk of developing hyperglycaemia as a result of cancer treatment, including glucocorticoids, and how to recognise it
• check baseline HbA_1c and random venous plasma glucose (RPG) before starting glucocorticoid therapy
• educate patients to be aware of symptoms of hyperglycaemia (Box 3)
• rule out and treat DKA or HHS if RPG or CBG is ≥20.1 mmol/l, or reaches this level at any point in the treatment, or if there are symptoms suggestive of DKA or HHS.

Starting Anticancer Treatment in Patients Who do not Have a History of Diabetes

In addition to the steps above, when anticancer treatment of any type is started in patients with no history of diabetes, the GP should be informed when:

• RPG is ≥12 mmol/l before starting glucocorticoids
• HbA_1c is ≥42 mmol/mol for management of hyperglycaemia—but do not delay urgent SACT or glucocorticoid treatment.

Starting Glucocorticoids or Systemic Anticancer Therapy in Patients Who do not Have a History of Diabetes

In addition to the steps above, the following steps should also be taken when anticancer treatment, including chemotherapy, targeted agents, or glucocorticoids, is started in people without a history of diabetes:

• educate patients and healthcare professionals that glucocorticoids typically increase blood glucose levels 4–8 hours after ingestion, leading to peak blood glucose between midday and evening meals if administered in the morning^56,57
• be aware that 10% of cancer patients develop glucocorticoid-induced diabetes once they have been administered supra-physiological doses of steroid (>5 mg prednisolone or equivalent),⁵⁰ and that this is dose dependent⁵⁸
• add individuals with glucocorticoid-induced hyperglycaemia to the diabetes register (or a similar system) for appropriate and ongoing follow up
• monitor RPG at each treatment visit
• educate patients to check CBG at least once daily. This should preferably be before a midday or evening meal or, alternatively, 1–2 hours after a midday or evening meal⁴⁹
• consider commencing gliclazide 40mg if raised blood glucose is ≥12 mmol/l on two occasions (the second occasion can be a repeat glucose level within 24 hours)
• educate patients to monitor CBG four times daily, with a mix of pre- and post-meal tests on different days. CBG monitoring should continue if CBG remains >12 mmol/l after discontinuation of glucocorticoids
• inform people who develop diabetes, and healthcare professionals, that target CBG is 6–10 mmol/l, with an acceptable range of 6–12mmol/l. However, individuals receiving end-of-life care may not need tight glycaemic control, and a range of 6–15 mmol/l is acceptable⁵⁹
• gliclazide may require frequent and significant increases in dose to reduce glucose levels, particularly in patients on high-dose steroids⁴⁹
• inform diabetes care providers if blood glucose is persistently raised
• if gliclazide maximum dose is not enough to control hyperglycaemia, insulin may be needed; contact the diabetes team
• gliclazide can cause hypoglycaemia in people who develop diabetes that have an estimated glomerular filtration rate (eGFR) <30 ml/minute/1.73m²; start insulin treatment in liaison with the diabetes team
• reduce the treatment of diabetes as glucocorticoids are reduced; a weekly 5 mg reduction of prednisolone from 20 mg may require a 25% reduction in insulin dose (if used), or a 40 mg reduction in gliclazide
• stop monitoring CBG if the readings are persistently <12 mmol/l and glucocorticoids have been discontinued
• see the JBDS guidelines on management of hyperglycaemia and steroid (glucocorticoid) therapy for glucose monitoring advice.⁵⁶

Starting Systemic Anticancer Therapy Without Immune Checkpoint Inhibitors in Patients Who do not Have a History of Diabetes

The following additional steps should be taken when starting SACT without immune checkpoint inhibitors (ICPs) in patients who do not have a history of diabetes: 

• advise patients to check CBG a couple of times a day at different times of the day (a mix of pre- and post-meal glucose)
• inform and educate patients and healthcare professionals about the target CBG (generally 6–12 mmol/l is acceptable)
• if plasma glucose or CBG are consistently <12 mmol/l, consider cessation of testing unless there is a change in treatment
• check RPG at each visit or each cycle of treatment, and repeat within 24 hours if high
• if blood glucose levels are raised on two consecutive occasions, screen for symptoms of hyperglycaemia or ketosis (Box 3)
• commence gliclazide 40 mg in the morning and ensure the patient has enough strips and a functioning glucose meter to check CBG levels; inform the patient’s GP
• if plasma glucose is >20 mmol/l, or there are symptoms of DKA or HHS, inform the diabetes team and start insulin treatment
• a number of anticancer therapies are known to cause nephrotoxicity and hepatotoxicity, and both complications may require adjustment of diabetes treatment.

Starting Immune Checkpoint Inhibitors in Patients Who do not Have a History of Diabetes

The following additional steps should be taken when starting treatment with ICPs in patients who do not have a history of diabetes: 

• educate healthcare professionals and patients that ICPs can cause new diabetes, particularly if combination therapies are used^60,61
• educate patients and healthcare professionals that ICP-induced hyperglycaemia usually behaves like type 1 diabetes, and that up to 75% of people who develop ICP-induced hyperglycaemia may present as DKA or HHS^62,63
• if plasma glucose or CBG is ≥20mmol/l, or if there are suggestive symptoms (sweetish breath or deep breathing), rule out DKA or HHS; this often develops precipitously, and in one in 20 people it can occur when glucose levels are <13 mmol/l (Table 1)
• measure pancreatic antibodies⁶⁴
• withhold ICP if there is evidence of an ICP-induced diabetes emergency⁶⁵
• educate patients and healthcare professionals that, although ICP-induced hyperglycaemia is less common than glucocorticoid-induced hyperglycaemia, it is almost always irreversible and will require lifelong treatment
• almost all patients require insulin therapy; refer urgently to the diabetes team and admit patients into hospital if they have HHS or DKA
• once the patient has been regulated with insulin substitution, consider restarting ICP
• educate patients and healthcare professionals that ICPs can also cause hypoadrenalism which can potentially cause hypoglycaemia.

Hypoglycaemia

Refer to the JBDS hypoglycaemia guidelines or local hospital guidelines for the management of hypoglycaemia in adults with diabetes.⁶⁵ Consider raising the threshold of glucose targets to 6–15 mmol/l to avoid hypoglycaemia in some patients. The following additional steps should be taken to avoid hypoglycaemia by educating patients and healthcare professionals that:

• people receiving end-of-life care (particularly those with poor performance status >2) may not require tight blood glucose control⁶⁶
• people with ICP-induced insulin deficiency may have labile glucose control and are at risk of hypoglycaemia⁶⁷
• ICP can also cause hypopituitarism, leading to hypoglycaemia due to adrenal insufficiency associated with hypotension, hyponatraemia, and hyperkalaemia. Adrenalitis due to primary adrenal insufficiency is very rare
• other causes of pituitary and adrenal insufficiency include metastasis, surgery, radiation, treatment with the azole group of antifungals, and abrupt cessation of glucocorticoids
• somatostatin analogues such as octreotide and lanreotide are potent inhibitors of growth hormone and glucagon in addition to insulin. They can therefore cause refractory hypoglycaemia as well as hyperglycaemia
• patients with huge tumour mass with multiple liver metastases are at high risk of tumour-induced hypoglycaemia
• certain haematological SACT, such as lenalidomide and bortezomib, can cause hypoglycaemia, particularly in people with diabetes
• liver disease and renal impairment can lead to hypoglycaemia
• poor oral intake can lead to hypoglycaemia
• people on gliclazide are at higher risk of hypoglycaemia
• drivers need to report any episodes of severe hypoglycaemia requiring help from a third party to the Driving and Vehicle Licensing Agency.

Additional steps should be taken when anticancer treatment (SACT or glucocorticoids) is started in people with pre-existing diabetes.

Managing Nausea and Vomiting

• people with diabetes receiving emetogenic chemotherapy should be offered a neurokinin antagonist (for example, aprepitant) with a long acting 5-hydroxytryptamine 3 antagonist (for example, ondansetron)
• people with diabetes should be made aware of the likely exacerbation of hyperglycaemia while on antiemetic therapy
• consider the use of a glucocorticoid in the first cycle, and reduce doses, or withdraw completely, based on the patient’s emetic control and on blood glucose management.⁶⁸

Managing Diabetes

• document the type of diabetes
• document any complications of diabetes, and whether hypoglycaemia unawareness is present
• ensure that individuals with known diabetes undertake regular CBG monitoring upon commencing SACT. Educate them that they may have to do more frequent testing if CBG deteriorates
• monitor HbA_1c every 3 months while receiving SACT, and RPG at each treatment visit or cycle
• inform the diabetes team that SACT is being started, and that glycaemic control may deteriorate and require prompt specialist support
• educate all members of the team that rapid antidiabetic therapy changes may be required when commencing high dose glucocorticoids or SACT to maintain CBG between 6–12 mmol/l
• if CBG is ≥20.1 mmol/l, consider DKA or HHS and refer to the diabetes team
• education about modifications to antidiabetic therapy may be necessary if CBG is 12–20mmol/l
• patients on dietary treatment alone, or on medications other than sulphonylureas or meglitinides (insulin secretagogues), may need to start gliclazide 40 mg in the morning and adjust the dose based on CBG before the evening meal, if blood glucose is 12–20 mmol/l on two consecutive occasions. The second of these consecutive occasions can be within 24 hours of the first high reading. Inform the diabetes team
• if CBG is >20 mmol/l on any occasion, or if there are any symptoms of DKA or HHS-like sweet breath or deep breathing (one in 20 people can have DKA or HHS with glucose levels <13 mmol/l), liaise with the diabetes team and admit the patient to hospital for treatment
• if CBG remains >15 mmol/l in diabetes patients already on sulphonylureas such as gliclazide, the dose may need to be increased at each treatment visit to a maximum of 240 mg in the morning and 80 mg in the evening (or 120 mg modified release), with the aim of maintaining CBG at 6–15 mmol/l; inform the diabetes team
• educate all members of the team that gliclazide can cause hypoglycaemia, and how to recognise and treat it
• educate and prepare patients receiving glucocorticoids who are on oral antidiabetic therapy that they may need insulin, as diabetes control may deteriorate⁵⁶
• educate and prepare people with type 2 diabetes who are on oral therapy and receiving ICP that glycaemic control can suddenly deteriorate, and that insulin may need to be initiated
• insulin-treated patients may need higher doses of insulin
• when plasma or CBG is >12 mmol/l on two consecutive occasions, screen for symptoms and test for DKA and HHS
• liaise with the diabetes team on up-titration of insulin dose^49,56,69
• if unable to contact the diabetes team, titrate insulin dose upwards by 10–20%; however, an increase of 40% is usually required to maintain glycaemic control in people on glucocorticoids^49,69
• monitor CBG more frequently, and reduce insulin appropriately to avoid hypoglycaemia
• check that patients are aware of sick-day rules, and of the need to adjust therapy or seek help when not well
• do not omit basal insulin in people with type 1 diabetes to avoid DKA, even when oral intake is limited. The patient may need hospitalisation and intravenous dextrose if oral intake is not enough.

Steps to be Taken before Scans

• for contrast scans, discontinue metformin temporarily if contrast is being used, or if GFR is <30 ml/min
• glycaemic excursions can affect the quality of positron emission tomography scans, so aim for glucose levels in the range of 4–11 mmol/l and avoid oral antidiabetic agents for 4–6 hours before the scan. Consider giving a correction of rapid acting insulin to people whose blood glucose is >12 mmol/l before the scan.

Recommendations on Nutritional Advice and Support for Patients

Patients should be advised to adopt a healthy balanced lifestyle.^70–72 Physical activity should be encouraged and advice on this should be individualised.

People with diabetes should be reminded to follow sick-day rules and to liaise with the diabetes and oncology teams if certain medications need to be stopped as part of sick day guidance. Resources are available to support patients with this:

• NHS: sick-day rules on how to manage type 2 diabetes if you become unwell with coronavirus and what to do with your medication
• Diabetes UK: Diabetes when you're unwell.

The following nutritional advice and support should be given:

• encourage standard food hygiene due to the high risk of infection during SACT
• advise on diet to maintain good glycaemic control, and on the need for increased protein intake for delayed wound healing during SACT
• refer to a dietician if carbohydrate awareness or counting is required to maintain glycaemic control in patients treated with insulin
• support people who are losing muscle mass, people with unexplained weight loss >5% in the previous 3–6 months, or those who have not eaten enough for >5 days and/or are likely not to eat enough in the next 5 days
  • provide oral nutritional support if oral intake remains poor, in the form of high calorie protein foods and snacks
  • relax the healthy balanced diet approach if that would help some calorie intake
  • replace carbohydrate with fat in some situations if that would help maintain weight⁷²
• provide enteral nutritional support in individuals who are malnourished and have inadequate oral intake or unsafe swallow but functioning gastrointestinal tract.⁷³ Refer to a dietician with expertise in diabetes⁷⁴
• provide parenteral nutrition in people who are malnourished with inadequate oral and/or enteral intake and a non-functioning, inaccessible, or perforated gastrointestinal tract.⁷³ Refer to a dietician with expertise in parenteral nutrition in people with diabetes. Monitor CBG frequently and refer to the diabetes team for an appropriate antidiabetic regimen
• consider and support home parenteral nutrition if appropriate⁷⁵
• monitor CBG more frequently, maintain healthy diet, and optimise diabetes treatment if glucocorticoids are being used to stimulate appetite
• refer to a dietician if the patient is following a restrictive diet, such as a ketogenic diet or fasting diets
• liaise with a dietician and the diabetes team for individuals with type 3c diabetes who will need pancreatic enzymes in addition to antidiabetic therapy
• advise people with diabetes at risk of hypoglycaemia about prevention and treatment. Generally, the advice is to take 15–20 g of fast-acting carbohydrate in the form of four to seven glucose tablets, 150–200 ml of pure fruit juice, or five jelly babies.⁶⁵ This should be followed up by a meal or snack containing slower-acting carbohydrate.⁶⁵

Multidisciplinary Working

It is vital that the JBDS guidelines are shared between clinical oncologists, diabetologists, and endocrinologists so that standardised treatment can be offered while maintaining patient safety. The JBDS recommends a weekly multidisciplinary team meeting between concerned specialists to share best practice and agree on decisions in complex cases.

Potential Barriers to Implementation of this Guideline

Many good guidelines exist in the NHS, but their implementation is patchy as different trusts and clinicians use slightly different methods, leading to the potential for confusion and patient harm. JBDS guidelines are supported by most of the leading societies in the UK, and are therefore likely to be followed, provided that clinicians are aware of them. 

The NHS is currently facing a major workforce crisis and clinical improvement may depend upon ease of implementation, which can be supported by prompts on the electronic systems of various trusts. The current post-pandemic backlog of patients waiting to start or continue with their treatment journey also poses a challenge. Most junior doctors access information and clinical guidelines on their phones, and the recommendations in these guidelines could be incorporated into the micro-guides used by different trusts. Availability of A4 laminated charts in clinical areas could also assist implementation.