24
Diabetes and the Cancer Patient
Jane M. Geraci, MD, MPH
Mary Ann Weiser, MD, PhD
The prevalence of diabetes mellitus has more than
doubled in the United States since 1980; cur-
rently, an estimated 20.8 million people living in
the United States have diabetes, and for every two
persons with diagnosed diabetes, there is one to
two with undiagnosed diabetes.1 Based on hos-
pital records, it is estimated that approximately
20% of patients with various cancers are known
to have diabetes.2 It is well known that hospital
records underreport the prevalence of diabetes
mellitus.3,4
The prevalence of diabetes and cancer
increases with age; there may be common risk
factors for diabetes and some cancers; diabetes
may predispose patients to certain cancers; and
cancers and cancer therapies may worsen or
precipitate diabetes. Cancer prognosis may be
affected by glycemic status. Acute hyperglycemic
complications of diabetes may interfere with
timely cancer therapy, including surgery and che-
motherapy. In a person with uncontrolled dia-
betes, the risks of infections may be higher and
wound healing impaired. Cancer patients with
diabetes may be at a higher risk of developing
certain complications of cancer chemotherapy.
Timely diagnosis of diabetes is a prerequisite
for its optimal management. Fasting plasma glu-
cose is sufficient to screen for diabetes mellitus. A
fasting plasma glucose g126 mg/dL following
Copyright © 2000. PMPH USA, Ltd.. All rights reserved.
at least 8 hours (overnight) without caloric intake
or a casual or nonfasting plasma glucose concen-
tration g200 mg/dL with symptoms of diabetes
clinches the diagnosis of diabetes, if confirmed on
another day by at least one of the two tests. Some
of the classic symptoms of diabetes, such as
unexplained weight loss, may be confounded by
the presence of the cancer.
Randomized controlled clinical trials in both
type 1 and type 2 diabetes have conclusively dem-
onstrated that tight blood glucose control reduces
the risk of long-term complications of diabetes.5–7
Tight blood glucose control with intensive insulin
Medical Care of Cancer Patients, edited by Sai-Ching Jim Yueng, et al., PMPH USA, Ltd., 2000. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/cvtisr-ebooks/detail.action?docID=3386898.
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Pankaj Shah, MD
Naifa L. Busaidy, MD
Melissa Hamilton, RD
therapy has also been shown to reduce morbidity
and mortality among critically ill patients.8 In
contrast to the large evidence base that guides
optimal diabetes management, there is very little
research into effective management approaches
and associated outcomes for patients with both
cancer and diabetes mellitus. In this chapter, we
review (1) the pathophysiology of both diseases,
highlighting common pathways; (2) the available
evidence indicating that hyperglycemia affects
some cancer and cancer treatment outcomes; (3)
what is known about the effect of cancer therapy
on diabetes; and (4) management of diabetes in
a cancer patient, including nutrition therapy and
the care of diabetics with advanced cancer.
Diabetes and Cancer Outcomes
There is increasing evidence that patients with
diabetes or impaired glucose tolerance may be
at an increased risk of cancer, cancer recurrence,
cancer-related mortality, and all-cause mor-
tality.9–11 Specifically in large cohort studies,
pancreatic, colon, breast, liver, and endometrial
cancers have been shown to occur more fre-
quently in patients with a history of diabetes
mellitus. For certain malignancies, the presence
of diabetes and/or impaired glucose tolerance
may also adversely affect the response to cancer
treatment. Patients with stage II–III colon cancer
treated with adjuvant chemotherapy had a lower
5-year survival rate if they had diabetes.12
Diabetes was found to be an independent risk
factor for a shorter overall (19.8 vs 29.2 months)
and disease-free survival (11.3 vs 17.2 months)
in patients with resectable pancreatic cancer
receiving adjuvant or neoadjuvant treatment,
in addition to surgery.13 Patients with acute
lymphocytic leukemia treated with hyper-CVAD
(fractionated cyclophosphamide, vincristine,
Adriamycin, and dexamethasone) (N=278) had
a shorter median remission duration and (24 vs
52 months) overall survival (29 vs 88 months)
when they had diabetes or hyperglycemia.14
209
Chemotherapy and radiotherapy may be
more toxic in people with diabetes. It is believed
that diabetes predisposes patients to neuropathy
induced by chemotherapies.15 Likewise, late-
radiation toxicities are higher in people with
diabetes.16
There is a lack of randomized trials investi-
gating if optimal treatment of diabetes affects
cancer outcomes. It is likely that the targets of
therapy and optimal choice for diabetes treat-
ment may well be cancer type, site, and stage
dependent, with a great deal of individualization
when life expectancy is very short.
Insulin, which is typically elevated in the
early stages of type 2 diabetes, is a potential
growth factor for malignancies. Insulin reduces
sex hormone–binding globulin levels, thereby
increasing concentration of free estradiol, which
may play a role in inducing neoplasia of the breast,
endometrium, and ovary. Insulin cross-reacts
with the insulin-like growth factor 1 (IGF-1)
receptor; the latter activates intracellular tyrosine
kinase activity, which stimulates cell growth. In
cell culture, growth of virtually all cell lines is
stimulated by insulin and IGF-1. Tumor cells may
also lose their ability to down-regulate insulin-
binding sites and become more sensitive to the
stimulatory effects of insulin.17 In vitro insulin
may also inhibit the apoptotic effects of certain
antineoplastic therapies, such as anti–epidermal
growth factor receptor monoclonal antibody.18
However, the concentration of insulin used in in
vitro models is several orders of magnitude higher
than the prevailing insulin concentrations in
patients with diabetes. In vivo insulin has been
shown to ameliorate enhanced tumor growth in a
streptozocin-induced diabetic hamster model.19
Therefore, whether insulin promotes cancer
growth in vivo is still an open question.
Hyperglycemia may also directly affect
tumor cell biology. Tumor cells tend to exhibit
increased glycolytic metabolism.20 Glycolysis per
se may promote carcinogenesis.21 Hyperglycemia
 210 Chapter 24
may also reduce the sensitivity of certain tumor
cell lines to certain types of chemotherapy.
Wound Healing and Diabetes
Uncontrolled diabetes is associated with more
frequent infections and a tendency toward more
complicated infections.22 Poor control of diabetes
is associated with impaired white blood cell func-
tion,23 and infection rates have been decreased
with more aggressive control of blood glucose.24
Significant hyperglycemia is associated with poor
collagen content and wound healing.25
Pathophysiology of Diabetes in
Cancer
Certain neoplasms may produce hormones
with counterinsulin (eg, glucagon, adrenocorti-
cotropic hormone [ACTH], cortisol, catechol-
amine) or insulin-suppressant (somatostatin)
actions. Diabetes may be one of the characteris-
tics of these syndromes.26–29 Acute diabetic com-
plications have been reported with several of
these tumors (glucagonoma,30 ACTH-producing
tumors,31 and pheochromocytoma).32 More com-
monly, on the other hand, malignancies not typi-
cally associated with secretion of the hormones
mentioned above are associated with a new diag-
nosis of diabetes,33 best exemplified for pancreatic
cancer.
Systemic Factors
Prevailing plasma glucose concentrations are a
result of the balance of the amount of glucose
entering the circulation and the amount leaving.
Increased glucose entering, reduced leaving, or
both can cause hyperglycemia. Cancers are asso-
ciated with increased glucose production and glu-
coneogenesis34,35 and decreased glucose uptake.36
Cancers, cancer therapies, and concurrent
infections are associated with elevated free fatty
acids.37,38 Elevated free fatty acid concentration
has been shown to be associated with reduced
glucose use and increased glucose production,
with increased gluconeogenesis.39–41 Many
malignancies and several chemotherapies are
associated with catabolic states and with elevated
Copyright © 2000. PMPH USA, Ltd.. All rights reserved.
lactic acid concentrations.42,43 Elevated lactic
acid concentrations, in turn, promote hepatic
gluconeogenesis and ketogenesis.44
Cytokines and other substances released
from the cancers45 can cause hyperglycemia by
inducing insulin resistance. Certain infections
may be associated with increased cancer and dia-
betes occurrence; for example, hepatitis C infec-
tion is associated with both (hepatocellular)
cancer and diabetes mellitus.46 Plasma cortisol
and glucagon concentrations in patients with
malignant tumors are significantly increased
when compared with patients with benign sur-
gical disorders,47,48 causing anorexia, enhanced
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tumor protein synthesis, stimulated tumor
growth,49 and an increased rate of appearance
of glucose in the blood.
Effects of Cancer Treatment on
Diabetes Mellitus
As summarized in Table 1, several drugs used for
cancer may have adverse effects on glycemic con-
trol. Glucocorticoids used as antitumor agents or
for symptom relief and prevention of hypersensi-
tivity reactions worsen glycemic control in people
with established diabetes and may precipitate dia-
betes, especially in people predisposed to type 2
diabetes. In our experience, this is related to the
dose and potency of the glucocorticoid. The
mechanisms are multiple, including increased
hepatic glucose output and decreased peripheral
glucose use, in addition to reduced insulin
secretion.50 Interferon-a2 is used to treat chronic
myelogenous leukemia and melanoma; hypergly-
cemia is one of the main side effects of this drug.
Some patients who develop interferon-alpha2
induced hyperglycemia require insulin for
therapy. Therefore it is believed that Interferon-
alpha 2 induced hyperglycemia may be immune
mediated.51 l-Asparaginase is used to treat acute
leukemia and lymphoma; it is thought to cause
hyperglycemia through inhibition of insulin
activity or receptor synthesis.51 Octreotide is a
synthetic long-acting somatostatin analogue; it
inhibits secretion of several hormones, including
insulin,52 and can cause hyperglycemia. Tacro-
limus is an immunosuppressive drug used in
both solid organ and stem cell transplantation.
Hyperglycemia requiring insulin treatment has
been observed in 5% of patients receiving it for
graft-versus-host disease.53
Imatinib (Gleevec) binds to the BCR-ABL
gene at the adenosine triphosphate binding
Table 1 Pharmacologic Agents in Oncology that May Affect Blood Glucose
Agent Current Uses
Glucocorticoids Chemotherapy for acute leukemia, Hyperglycemia
  lymphoma; symptomatic brain   production; decreased
  metastasis, nausea and vomiting,   peripheral glucose use;
  pain; premedication for taxanes   decreased insulin
  and many other regimens   effectiveness
Interferon-a2 Metastatic melanoma Hyperglycemia
l-Asparaginase Acute leukemia Hyperglycemia
  insulin receptor synthesis
Octreotide Carcinoid, pituitary tumors Hyperglycemia
(Sandostatin)   and VIP-secreting tumors
Tacrolimus GVHD Hyperglycemia and Inhibition of insulin secretion,
(Prograf)   new-onset   peripheral insulin resistance
  insulin-requiring
  DM
Imatinib CML; GIST Improvement of
(Gleevec)   hyperglycemia   insulin resistance
CML = chronic myelogenous leukemia; DM = diabetes mellitus; GIST = gastrointestinal stromal tumor; GVHD = graft-versus-
host disease; VIP = vasoactive intestinal peptide.
site. This results in an inhibition of the activity
of BCR-ABL gene and elimination of these
BCR-ABL gene (Philadelphia chromosome) posi-
tive cells.54 Imatinib may decrease blood glucose
in patients with known diabetes, sometimes in
a dramatic fashion,55 by an as yet unknown
mechanism.
Specific surgical procedures (pancreatectomy
for pancreatic and gastrointestinal cancers) and
radiotherapy to the abdominal region may also be
associated with new-onset diabetes mellitus.56
Lifestyle Changes and Diabetes
Cancer-related fatigue, weakness, decreased
muscle strength, anxiety, depression, and changes
in body image are associated with decreased phys-
ical activity and can reduce insulin sensitivity.57
Cancer patients have been advised to rest by the
family and physicians, despite the benefits of
regular physical acivity.58 Prolonged decreased
physical activity can cause disuse muscle atrophy
and a further decline in activity.
Cachexia
Malignancies are associated with varying degrees
of cachexia, with pancreatic and gastric cancer
causing it most often. Unlike weight loss induced
by regular exercise and dietary intervention,
cachexia-associated muscle wasting leads to
muscle weakness and fatigue, resulting in
decreased physical activity and reduced glucose
use. Infections are also common in cachectic
persons because of poor immune function,
complicating the insulin resistance of cachexia.
Nutrition Supplements
Nutritional supplements, including tube feeding
and intravenous parenteral nutrition, can increase
plasma glucose concentrations, especially if the
Side Effect Possible Mechanisms
Increased hepatic glucose
Decreased insulin secretion
Immune mediated
Inhibition of insulin or
Inhibition of insulin secretion
Unknown; possibly reduced

amount of glucose delivered is more than the
body’s ability to use it. Provision of extra insulin
may not be able to compensate if overwhelming
excess calories are provided to these patients with
low muscle mass and diminished ability to use
glucose.
Managing Diabetes in Patients with
Cancer
Treating diabetes in a person with active cancer is
often complicated by the very presence of cancer,
cancer therapies, and treatment side effects, such
as anorexia, nausea, and weight loss. Acute com-
plications of diabetes and urgency of treating
severe hyperglycemia often delay the treatment
of cancer. The presence of diabetes increases the
stress of cancer and cancer management.
The goals of diabetes management have
become more stringent, with rapidly accumu-
lating evidence of the benefits of tight glycemic
control in preventing chronic complications from
diabetes. However, in the presence of a severe ill-
ness, such as cancer, undergoing active therapy,
the benefits of tight glycemic control are not clear.
Extrapolating from the data, one could argue that
glycemic control should be targeted to as close to
normal as possible, without increasing hypogly-
cemic events or adding significant stress to the
patient. Plasma glucose concentrations should
be kept below 200 mg/dL (blood glucose below
180 mg/dL) since concentrations higher than
that increase the risks of infection, poor healing,
and possibly the risks of acute hyperglycemic
complications.
Diabetes Education
Diabetes mellitus should not be labeled as “hyper-
glycemia” unless the specific or another cause of
hyperglycemia is not likely to recur. Even if hyper-
glycemia is apparently attributable to a specific
medication or stress, patients and their physicians
should realize that such situations can and pos-
sibly will arise again during the subsequent treat-
ment cycles. It is safer if a patient believes that she
or he has “diabetes” and continues to monitor
periodically and more frequently when ill. In this
way, severe hyperglycemia is prevented by early
Copyright © 2000. PMPH USA, Ltd.. All rights reserved.
recognition and intervention. Family and care-
givers should understand that adequate diabetes
education and management facilitate timely eval-
uation and treatment of the cancer and reduce the
risk of infection, poor wound healing, and
unplanned hospitalizations and doctors’ visits.
Skills learned during this time would be helpful
for a healthy life after cancer.
It is ideal that patients and their family
members acquire the skills of diabetes self-
management. These include blood glucose moni-
toring, techniques of insulin injection, knowledge
and skills of correcting the insulin dose for blood
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glucose, and self-adjustment of insulin doses
based on a pattern emerging from a few days of
monitoring. Hypoglycemia prevention and man-
agement plans (including glucagon injection
technique if appropriate) and management plans
for the days when sick, traveling, or fasting for
tests should be in place for the patient. An identi-
fication card listing the current medicines and
simple instructions for what to do when the
patient is found with an altered mental status
should be carried by patients taking agents that
can cause hypoglycemia.
Nutrition
Medical nutrition therapy plays a central role in
the treatment of diabetes mellitus. Medical nutri-
tion therapy involves a comprehensive nutrition
assessment to evaluate current nutritional status.
In addition to the diet history, the nutrition
assessment should include the patient’s medical
history, social history, physical data including
height and weight, and laboratory data.59
In a cancer patient, the nutrition assessment
should also consider cancer treatment modalities
(such as surgery, chemotherapy, and radiation)
and management of their side effects. In general,
the overall goal for a person with diabetes and
cancer is to maintain optimal metabolic control
and achieve a weight that is appropriate for
the patient.59,60 Some patients with cancer and
diabetes are overweight and are advised to lose
weight, so caloric restriction may be appropriate
for them. Others may be losing too much weight
or losing weight too quickly, and in such
situations, weight maintenance or improvement
may be a nutritional management goal. There-
fore, these patients require oral nutritional
supplements in addition to a healthy diet.
A registered dietitian plays an important role
in making recommendations that are specific to
the individual and should provide a strategy for
achieving a healthy diet and lifestyle.60 The dieti-
tian should participate in monitoring patient
progress in establishing a healthy diet, main-
taining a healthy weight, and achieving adequate
glycemic control. If established goals have been
met, then there may be no need for further
change.
In general, carbohydrate and monoun­
saturated fat should provide 60 to 70% of esti-
mated energy requirements, protein should be
approximately 15 to 20% of total caloric intake
(1–1.5 g/kg body weight), and fat should be lim-
ited to less than 30% of total caloric intake, with
less than 10% of total caloric intake from satu-
rated fat. Diets such as those that are “low sugar”
or “sugar free” or have “no concentrated sweets”
are not synonymous with medical nutrition
therapy for diabetes and are not indicated for
glycemic control. Sucrose does not increase
glycemia to a greater extent than isocaloric
Diabetes and the Cancer Patient 211
amounts of starch. Therefore, sucrose and
sucrose-containing foods do not need to be
restricted by people with diabetes and should
be eaten in the context of a healthy diet.60
If diabetes is being treated with sulfonylurea,
other insulin secretagogues, or intermediate-
acting or mixed insulin, the timing of meal and
distribution of carbohydrate intake through the
day are important, with the aim of preventing
both significant hyper- and hypoglycemias.
Spacing of meals, increasing fiber intake, and not
skipping meals are critical. When actively treated
cancer patients have anorexia, nausea, dysphagia,
or other complications preventing timely food
intake, they are encouraged to consume culturally
appropriate foods that can be easily swallowed,
retained, and digested. In such a setting, oral
nutritional supplements may be most convenient.
Alternatively, they may also need a change in their
pharmacologic treatment of diabetes to avoid
hypoglycemia.
If a person with diabetes needs intensive
insulin therapy, prandial (meal related) insulin
may need to be titrated to the total carbohydrate
intake in the meal rather than the source or the
type of carbohydrate. Initially, it may be conve-
nient to teach the patient and the family to keep
the carbohydrate content of each meal consistent,
and this can be achieved by learning basic carbo-
hydrate counting and meal exchanges. In this
way, insulin doses can be titrated quickly. If
required, later they can learn and work with
the carbohydrate to insulin ratio.
Use of nutritional support may necessitate
changes in the therapeutic regimen for diabetes.
For example, patients being tube-fed overnight
may need “prandial” insulin before their tube
feeds in the form of Neutral Protamine Hagedorn
(NPH). An enteral or parenteral nutritional sup-
plement provides calories through an unphysi­
ologic route and pattern, without a concomitant
increase in incretin hormones; therefore, inade-
quate insulin concentrations in relation to the
carbohydrates are provided. This, along with
insulin resistance and relative insulin deficiency
induced by sickness, cancer, and cancer therapies,
necessitates careful calorie assessment and judi-
cious provision of insulin. Broadly, wherever pos-
sible, regular food taken by mouth is better than
enteral tube feeding, and the latter is better than
parenteral nutrition. Parenteral nutrition should
be restricted to situations with proven benefits or
in a clinical trial setting. Parenteral feeding should
be ramped down quickly whenever enteral or oral
feeding can be resumed.
In-Patient Diabetes Management
Insulin is the mainstay of therapy in the hospital.
Unpredictable oral intake makes use of insulin
secretagogues best avoided in the inpatient
setting (Table 2). Nausea from other medications
 212 Chapter 24

Table 2 Types of Oral Glucose-Lowering Medications

Class name
Generic Name (Brand Primary Action Contraindications Adverse Effects Benefits Implications for
Names) Actively Treated
Cancer Patients
Biguanides Metformin (generic, Decreases hepatic Renal dysfunction Nausea, diarrhea, Modest weight May cause confusion:
  Glucophage,   glucose production,   (high creatinine),   weight loss   loss   GI side effects and
  Glucophage XR)   reduces appetite,   cardiovascular shock,   weight loss can be
  improves glucose   acute myocardial   confused as the
  uptake by muscles   infarction, septicemia,   effect of cancer or
  and fat   congestive heart failure,   its therapy
  acute or chronic Shown in correlative
  metabolic acidosis   and animal studies
  to be associated
  with possible
  cancer prevention
Often stopped for
  ≈48 hours before
  contrast
  radiography

Thiazolidinediones Pioglitazone (Actos) Increases glucose uptake Heart failure (especially Water retention, Does not cause Weight gain—may
Rosiglitazone (Avandia)   by muscle and fat and   NYHA grade III and IV)   anemia, weight   hypoglycemia   be desirable in
  reduces glucose   gain   some
  production by the Heart failure and
  liver.   fluid retention
  may be confused
  as the effects of
  cancer therapy
Actively being
  investigated for
  anticancer
  properties for
  several cancers

a-glucosidase Acarbose Inhibits enzyme that Chronic intestinal Flatulence, abdominal Hypoglycemia GI side effects and
inhibitors   (Precose/Glucobay)   facilitates the   disorders, severe renal   bloating, diarrhea   does not occur   weight loss
Miglitol (Glyset)   breakdown of complex   impairment (creatinine   when used   confused with
  sugars to glucose in the   clearance <25 mL/min)   alone   cancer or therapy
  small intestine; causes Treat hypoglycemia
  carbohydrate   with glucose, not
  malabsorption   sucrose or other
  carbohydrates

Sulfonylureas and Glyburide (generic, Enhances insulin Most contraindicated in Hypoglycemia: Most accumulated May be difficult to
other insulin   Glynase, DiaBeta,   secretion   significant renal and   repaglinide,   experience   use during cancer
secretagogues   Micronase)   hepatic diseases   nateglinide, and   therapy: nausea
Glipizide (generic,   glipizide least likely   and anorexia may
  Glucotrol, Glucotrol   to cause   cause erratic
  XL), glimepiride   hypoglycemia;   intake, and
  (Amaryl)   chlorpropamide,   predisposition to
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Nateglinide (Starlix)   glyburide most   hypoglycemia

Repaglinide (Prandin)   likely In vitro studies imply
Hyponatremia:   anticancer action
  chlorpropamide,   of some
  glyburide   compounds and
  their derivatives
GI = gastrointestinal; NYHA = New York Heart Association.
Combination pills: metformin+glyburide (generic, Glucovance); metformin+rosiglitazone (Avandamet); metformin+glipizide (Metaglip).

and the risks of lactic acidosis in the inpatient medications take a long time to have a full effect, option for most patients with hyperglycemia or
setting with hypoxia, hypoperfusion, and are titrated upward slowly, and have a slow onset diabetes during hospitalization.
renal insufficiency increase the risk of adverse of action, especially with thiazolidinediones There is increasing evidence that near-
events with metformin use (see Table  2). Oral (TZDs). Therefore, oral drugs are not the best normoglycemia in the hospital has the potential

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 Diabetes and the Cancer Patient 213

for improved mortality and morbidity and
decreased health care costs. Insulin therapy itself
may have direct beneficial effects independent of
its effect on blood glucose.61 In December 2003,
the American Association of Clinical Endocri-
nology together with the American Diabetes
Association held a consensus conference on the
management of the hyperglycemic patient in the
hospital.62 Target blood glucose levels were deter-
mined from the available literature to be the fol-
lowing: on the inpatient wards, target plasma
glucose levels are <110 mg/dL preprandially,
with a maximum glucose of 180 mg/dL at any
time. In the intensive care unit (ICU) setting, a
goal of near-normoglycemia has been set to 80 to
110 mg/dL. Recently, the American Diabetes
Association, American College of Endocrinology,
American Association of Clinical Endocrinolo-
gists, and other organizations came together and
produced a document highlighting the impor-
tance of implementation of optimal diabetes
management for inpatients.63
In general, hospitalized diabetic patients
require both basal and prandial (mealtime or
bolus) insulin coverage, just as in the outpatient
setting. Sliding scale insulins are to be avoided
and actually increase the risk of hypoglycemia
and hyperglycemia compared with basal and
prandial insulin.64–66
Insulin needs to be adjusted once or twice
daily to account for the rapid changes that occur
in the hospital. Nausea, vomiting, changes in oral
intake, intermittent enteral tube feeding, intrave-
nous fluids, use of glucocorticoids, and parenteral
nutrition all necessitate frequent reassessment of
the doses. Illness-related insulin requirements
are high at the onset of an illness and decrease as
the illness improves (see Table 3 for the timing of
insulin delivery).
In the mechanically ventilated surgical ICU
patient, intensive glycemic control with a target
glucose of 110 mg/dL with intravenous insulin
has been shown to decrease mortality and mor-
bidity.8 Evidence strongly supports the use of
intravenous insulin for patients in diabetic keto-
acidosis and hyperosmolar coma. In addition,
we use intravenous insulin therapy during car-
diovascular surgery; after a stroke, myocardial
infarction, or organ transplantation; and for
many other patients who are difficult to control
with other regimens. An appropriate transition
protocol off the intravenous insulin drip to sub-
cutaneous insulin should be in place in the hos-
pital to avoid worsened hyperglycemia after the
drip is turned off. Various insulin protocols have
been published.67,68 Often endocrinologists, inten-
sivists, internists, and nutritionists need to work
in close collaboration with the primary team for
the management of the diabetic patient admitted
to the hospital.
Outpatient Diabetes Management
Insulin
Insulin is indicated in all patients with uncon-
trolled diabetes for whom oral drugs are con­
traindicated (see Table  2). In addition, because
of immediate onset of action, it is the most
appropriate mode for quick control of severely
uncontrolled diabetes, for example, glucose
>350  mg/dL or >250  mg/dL with ketonuria.
Treating outpatients with insulin using a “sliding
scale” is also inappropriate.
Most patients needing insulin will at least
require basal insulin; this can be in the form of
two doses of NPH or one to two doses of glargine
or detemir insulin. Many others will require split-
ting the dose, especially if the requirements are
higher than 30 U/d. Premixed insulins are handy
for brief therapies, such as the postprandial hyper-
glycemia induced by glucocorticoids. Ideally,
patients with poor beta cell reserve should be
treated with a combination of basal long-acting
insulin (detemir or glargine, to supply basal
needs) with rapid-acting insulin boluses (aspart
or lispro for prandial needs), a regimen called
basal-bolus or MDI (multiple daily injection of
insulin).
Adjustments of insulin doses are based on
the expected physiologic action of the insulin
and determination of the glucose pattern before
changing the doses. By definition, the basal insulin
dose is intended to keep glucose stable when
no food, intravenous glucose, or other form of
insulin is given. Too often long-acting insulin
(detemir or glargine) is being used to control
both basal and prandial glycemia. This can lead
to serious hypoglycemia if scheduled nutrition is
interrupted.
Oral Antidiabetics
Sulfonylurea drugs are the least expensive but can
precipitate hypoglycemia if food intake is erratic.
Some, especially chlorpropamide and glyburide,
can cause hyponatremia. These are used with cau-
tion in the elderly, those with liver and kidney
diseases, and patients with erratic oral intake.
Metformin is an underused drug but cannot be
used in patients with liver, kidney, or heart failure.
Metformin and drugs that prevent conversion
of sucrose and starch to glucose (acarbose and
miglitol) can cause gastrointestinal symptoms,
which can be confused with complication of
cancer or its therapies. Peroxisome Proliferator-
Activated Receptors-gamma (PPAR-c) receptor
agonists (rosiglitazone and pioglitazone) can
cause fluid retention and weight gain. All oral
drugs are equally effective in bringing down

Table 3 Insulin
Duration of Action Subcutaneous Insulin
Rapid Short Intermediate Long
Common names Aspart (Novolog), lispro Regular (Novolin R, NPH (Novolin N, Glargine (Lantus),
  (Humalog), glulisine   Humulin R)   Humulin N)   detemir (Levemir)
  (Apidra)
Copyright © 2000. PMPH USA, Ltd.. All rights reserved.

Onset of insulin action 15 min 30 min to 1 h 2–4 h 2–4 h

Peak time of insulin action 1–2 h 2–3 h 4–10 h Peakless
Duration of insulin action 3–4 h 3–6 h 10–16 h 20–24 h
Recommended   Usually taken immediately Usually taken 30–60 Taken once or twice Usually taken twice or
administration of insulin   before or after eating   min before eating   daily   once daily
Visual appearance Clear Clear Cloudy Clear
Implications for cancer Best insulin when intake is Only form approved for Most accumulated Glargine binds avidly to
patients   unreliable; can be given   IV use   experience   IGF-1 receptor.
  after meal, based on food   Implications not clear.
  (carbohydrate) intake.   Detemir more reliably
  Safety in cancer patients   absorbed. Safety in
  not studied.   cancer patients not
  studied
IGF-1 = insulin-like growth factor 1; IV = intravenous; NPH = Neutral Protamine Hagedorn.

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 214 Chapter 24

Table 4 New Antidiabetic Classes

Class Generic Names Mechanism of Contraindications Indications Major Adverse How Used Implications for
(Brand Names) Action Effects Cancer Patients
Glucagon-like Exenatide (Byetta) Increases insulin Gastroparesis Type 2 diabetes Nausea, vomiting, Subcutaneous Weight loss may be
peptide 1   and reduces   adjunctive with   diarrhea, feeling 5 µg twice a day with   confusing
analogues   glucagon   metformin, a   jittery, dizziness,   meals, increased to “Benign thyroid
  response to   sulfonylurea, or   headache,   10 µg twice a day   C-cell adenomas”
  glucose; reduces   a combination   dyspepsia   after 4 wk, as   in rats
  gastric emptying,   of the two   tolerated May promote islet
  reduces appetite   differentiation
  and weight May inhibit apoptosis
  of certain cell types
Safety in cancer
  patients not studied
Amylin Pramlintide Reduced gastric Gastroparesis; Type 1 diabetes, Nausea, headache, Subcutaneous Weight loss may be
analogue   (Symlin)   emptying;   hypoglycemia   adjunct for   anorexia, Type 1 diabetes: 15 µg   confusing
  prevention of   unawareness   mealtime insulin   vomiting,   before each major Safety in cancer
  the postprandial   therapy Type 2   abdominal pain,   meal, increased by   patients not studied
  rise in plasma   diabetes, adjunct   fatigue, dizziness,   15 µg to 30 or
  glucagon;   for mealtime   coughing,   60 µg/dose, as
  improved satiety   insulin with or   pharyngitis   tolerated
  and potential   without a Type 2 diabetes on
  weight loss.   concurrent   insulin: 60 µg
  Suppresses   sulfonylurea   before each major
  glucagon and   agent and/or   meal, increased to
  stimulates insulin   metformin   120 µg/dose, as
  secretion.   tolerated

hemoglobin A1c (HbA1c) on an average by 1 per-
centage point (except acarbose, miglitol, nateg-
linide, and repaglinide being slightly less effective,
bringing down HbA1c by 0.5 percentage point).
For the management of diabetes in a patient
with cancer, usually metformin is the first-line
oral drug for obese individuals and glipizide for
nonobese individuals. Often TZDs are started as
the primary agent. Metformin can be combined
with glipizide or TZDs if either of them is not
effective alone. Often the most difficult problem
is to make sure that the adverse symptoms from
cancer or its therapies are not compounded by
the medications. Constant surveillance of the
contraindications is also required while using
these drugs in a cancer patient.
Newer Diabetes Treatments
Inhaled insulin, glucagon-like peptide 1 analogue,
and amylin analogue were recently added to the
options for diabetes management (Table 4). As
Copyright © 2000. PMPH USA, Ltd.. All rights reserved.
are required for such patients, but not
uncommonly, patients have very high fasting glu-
cose concentrations that will necessitate increasing
basal insulin doses. Management requires self-
monitoring of blood glucose to identify the pat-
tern of hyperglycemia and assess the treatment
regimen.
Management of Diabetes during Tube Feeding
If the G-tube feedings are being given by gravity
three to four times a day, subcutaneous regular
insulin before each tube feeding may be sufficient,
in addition to a basal insulin. However, if tube
feeding is being provided using a pump over a
length of time, we give NPH insulin before each
tube feeding. In addition, long-acting insulin
may also be given, for the basal insulin needs,
based on changes in blood glucose during the
time there is no tube feeding and no NPH insulin.
Administration of subcutaneous insulin should
be tapered off before feeding finishes to avoid
prevents onset of hyperglycemia if and when
the parenteral nutrition is interrupted. Whenever
diabetes is difficult to control and/or requires
high doses of insulin, the amount of total calorie
intake should be reassessed. Beyond a certain
limit, excess calories cannot be compensated by
extra insulin. This limit is often reached quickly
in an insulin-resistant sick person, especially
on unphysiologic nutritional support. Reassess-
ment of nutritional support may require indirect
calorimetric measurement of basal energy
expenditure.
Management of Diabetes in a Person with a Very
Short Life Expectancy
When life expectancy with terminal cancer is
brief, diabetes management is not aimed at pre-
venting chronic complications. It has been sug-
gested that dietary restrictions should be relaxed
and that blood glucose monitoring should be
performed only if the patient is conscious and

with the newer subcutaneous insulin analogues,
there are no good studies investigating the safety
and utility of these drugs in cancer patients.
Management of Glucocorticoid-Induced
Diabetes
There are no large studies investigating the
options for management of glucocorticoid-
induced diabetes. TZDs may be effective in pre-
venting and treating diabetes in such patients.
However, if hyperglycemia is significant, insulin
is invariably required. It is generally believed
that larger doses of prandial than basal insulin
hypoglycemia.
Management of Diabetes during Parenteral
Nutrition
Insulin is often added to the parenteral nutrition
solution, providing usually 1 unit per 10 g of glu-
cose (range 0.5–2 U/g glucose) in the parenteral
nutrition bag. This may not be sufficient to con-
trol glucose, and extra regular insulin is given
intravenously or subcutaneously as needed. In
patients with known diabetes and/or high insulin
requirements, many people will provide a small
dose of long-acting insulin subcutaneously. This
symptom control requires it.69,70 Insulin and other
diabetes medications should be reduced with
reducing appetite and intake and with the sole
aim of controlling symptoms to make the person
comfortable. Specialist input should be sought
for pain control, comfort care, and family
counseling.
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