Diabetes Management in Cancer Patients

Oncology (Williston Park). 30(6):565–570.

Table 1. Presentations of Diabetes Related to Cancer or Cancer Treatment

Table 2. Therapeutic Options for Diabetic Cancer Patients

Table 3. Acute or Subacute Complications of Diabetes and Diabetes Treatment Relevant to Oncology Care

Introduction

Hyperglycemia is a common challenge during cancer treatment and palliation. In addition, many patients with pre-existing type 1 or type 2 diabetes undergoing cancer treatment develop iatrogenic hyperglycemia with unique features. The most common example is steroid-induced hyperglycemia,[1] but several other scenarios are common and clinically important (Table 1). Special considerations are often necessary regarding standard lifestyle recommendations, optimal choice of antidiabetic drug (Table 2), and goals of therapy.[2] In patients with active cancer, the focus of hyperglycemia management shifts from preventing long-term complications toward avoiding acute and subacute outcomes, such as dehydration from polyuria, infection, catabolic weight loss, hyperosmolar nonketotic states (HNK), and diabetic ketoacidosis (DKA; Table 3).[3,4] It should be noted that the truly emergent conditions HNK and DKA are rare. The more common scenario of an asymptomatic severe elevation in blood glucose level (> 400 mg/dL, for example), although requiring a treatment plan with good hydration and close follow-up, does not typically require an emergency room visit or admission. Two representative clinical cases are presented here.

Clinical Vignette #1

Corticosteroid-induced hyperglycemia

A 53-year-old woman with a history of pre-diabetes and peripheral blood stem cell transplant for acute myelogenous leukemia (AML) presented with asymptomatic elevated random blood glucose levels. After transplant she developed graft-versus-host disease (GVHD) with liver injury, which was treated with 60 mg of prednisone daily, tapered gradually to 20 mg daily at the time of presentation 2 months later. Random serum glucose level was 396 mg/dL. Previously, all serum glucose levels had been less than 160 mg/dL until prednisone exposure, after which all were greater than 300 mg/dL. After peaking at 519 IU/L, alanine aminotransferase had declined to 158 IU/L.

She was started on twice-daily home glucose monitoring and glimepiride 1 mg daily. Home fasting blood sugar levels ranged between 120 mg/dL to 163 mg/dL, but pre-lunch and pre-dinner values ranged between 246 mg/dL to 378 mg/dL. Home monitoring frequency was increased to four times daily, glimepiride was stopped, and pre-meal insulin aspart sliding scale was started. Insulin aspart was titrated up to doses of approximately 10 units before meals, maintaining blood sugar levels between 86 mg/dL and 236 mg/dL. Due to low-to-normal bedtime glucose levels (70–100 mg/dL), pre-dinner insulin was stopped after a few days. After liver enzymes had normalized, metformin 500 mg daily was started, but could not be titrated up because of gastrointestinal side effects. After 1 month, the lunchtime insulin dose was eliminated, and after 2 months all insulin was stopped. At that time, she had a hemoglobin A1c (HbA1c) level of 6.5% on prednisone 12.5 mg daily and metformin 500 mg once daily. A prednisone taper creates a challenging “moving target” for insulin dosing.

Who is at risk for corticosteroid-induced hyperglycemia?

Corticosteroids are routinely included with chemotherapy as antiemetics or, more rarely, active components of chemotherapy. They are also used to manage autoimmune side effects or inflammation, particularly in central nervous system (CNS) lesions. Dexamethasone, the standard corticosteroid for antiemesis and CNS lesions,[5] possesses a half-life of 36 to 54 hours. Other corticosteroids have shorter half-lives; prednisone, for example, has a half-life of 5 to 6 hours. In patients with baseline impaired glucose tolerance, steroids cause postprandial glucose elevation.

This patient had a typical history, with pre-diabetes in the past followed by frank hyperglycemia during a period of sustained corticosteroid exposure.[6] However, it is important to recognize that corticosteroid-induced hyperglycemia can also occur very rapidly in patients with no prior history of diabetes.[7] Corticosteroid-induced diabetes generally resolves when corticosteroids are discontinued,[8] but it is nonetheless important to address in order to prevent short-term complications (Table 3). In some cases, severe sustained hyperglycemia directly impairs pancreatic endocrine function, a process that can result in HNK or DKA.

Treating and preventing corticosteroid-induced hyperglycemia

In this patient, short-term glycemic control to a goal range of 100 mg/dL to 180 mg/dL throughout the day was chosen. Routine home blood sugar testing revealed a typical pattern of prednisone-induced diabetes: near-normal fasting glucose levels followed by hyperglycemia during the day. Because corticosteroids increase sensitivity to carbohydrates, standard dietary counseling is appropriate. Pharmacotherapy was initiated due to marked hyperglycemia. Sulfonylurea therapy was briefly attempted, despite the risk of hypoglycemia, due to high potency and rapidity of effect. However, home glucose monitoring revealed variability over the course of the day, making short-term use of insulin the safest and most reliable option.

Insulin has two key advantages: potency and flexibility. Flexibility, in particular, was needed because the patient had near-normal fasting blood sugar levels but severe hyperglycemia during the day, which occurred because her metabolic function had recovered each morning before exposure to a new prednisone dose.[8] Most agents potent enough to control her blood sugar levels during the 6 to 12 hours of prednisone activity would have had the potential to cause nocturnal hypoglycemia. Hence, unlike most patients with diabetes, she required high doses of short-acting insulin but no basal insulin.

Even in cases where insulin is necessary, the whole range of diabetes drugs can be considered as adjuncts. Metformin has low cost, moderate effectiveness, and an excellent safety profile, and was likely helpful in weaning this patient off insulin. It should be avoided when estimated glomerular filtration rate (eGFR) is less than 30 mL/min and the patient is in hepatic failure. Mild transaminitis and hepatic metastases are not equivalent to hepatic failure (metformin is not contraindicated); in this case, we did ensure there was no evidence of ongoing GVHD of the liver before starting metformin.

Clinical Vignette #2

PI3K-induced hyperglycemia

A 78-year-old man reported for follow-up; he had a complicated medical history notable for squamous cell carcinoma of the chest (no evidence of disease), recently resected squamous cell carcinoma of the nasal passages, idiopathic diabetes insipidus, hypertension, hyperlipidemia, and gastroesophageal reflux disease. He initially presented to endocrinology with a myelodysplastic syndrome along with idiopathic diabetes insipidus (MRI of the sella unremarkable). He had received multiple blood transfusions for severe anemia (about 18 units in total). He had no prior or family history of pre-diabetes or diabetes; he started on a clinical trial with a MEK/phosphoinositide 3-kinase (PI3K) inhibitor 6 weeks prior.

Upon examination, the patient appeared frail and had an unsteady gait, with mild ankle swelling. His body mass index was 23.4, and labs showed a morning glucose (probably fasting) level of 185 mg/dL, with a normal eGFR. Glucometer check showed a post-lunch (random) glucose level of 227 mg/dL, with the patient noting that he vomited his lunch. The patient was asked to learn and institute home blood glucose monitoring but declined. He preferred to monitor glucose levels via study blood levels performed three times weekly.

The patient was started on a dipeptidyl peptidase 4 (DDP-4) inhibitor, as opposed to sulfonylurea, to avoid risk of hypoglycemia. Metformin was considered but not chosen due to potential for gastrointestinal complaints that could complicate interpretation of adverse effects from study drugs. A thiazolidinedione was not initiated due to the potential for volume overload given his ankle edema and history of multiple transfusions. A sodium-glucose co-transporter 2 (SGLT2) inhibitor was not initiated because these agents typically cause weight loss, undesirable in this frail patient. Furthermore, SGLT2 inhibitors may increase fall risk (via a decrease in volume), and this patient already had an unsteady gait. Insulin, initiated at a conservative weight-based dose (0.15 units per kg) for both the basal and for prandial coverage, would be a logical next option if needed. If oral intake is tenuous, rapid-acting insulin may be dosed after the meal, provided that the patient consumes more than 50% of a carbohydrate-containing meal.

Who is at risk for PI3K-induced hyperglycemia?

PI3K inhibitors frequently cause hyperglycemia because of an interruption in insulin signaling and secretion.[9] The main goals for this patient with advanced cancer are to prevent the sequelae of hyperglycemia (Table 3), particularly disqualification from the study protocol.

Treating and preventing PI3K-induced hyperglycemia

Standard lifestyle modification and antidiabetic drugs are all relevant to the management of PI3K-induced hyperglycemia. We suggest goals for fasting and random blood sugar levels for a patient like this to be < 160 mg/dL and < 200 mg/dL, respectively. However, some research protocols of investigational oncologic agents stipulate unnecessarily stricter targets. Also, given the ability to rapidly correct hyperglycemia related to PI3K/AKT/mTOR inhibitors, we have emphasized that clinical trial protocols allow a 1-week trial period of diabetes management, prior to dose interruption for hyperglycemia.[9]

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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