Abstract
Abstract
Hospice and palliative medicine practitioners frequently encounter diabetes and associated complications as comorbidities in end-of-life patients. As the patient with diabetes approaches end-of-life, there comes a time when tight glycemic control can not only prove of questionable benefit, but has the potential to cause harm. The medical literature offers little guidance on managing these complications appropriately. This article identifies three distinct classifications of patients with diabetes approaching the ends of their lives due to advanced illnesses. The authors propose a specific framework to guide management in patients with diabetes and advanced disease who are relatively stable, experiencing impending death or organ failure, or actively dying. The authors provide comprehensive information on commonly used diabetic medications, with necessary considerations and dose adjustments for these populations. The goal of the approach is to address individual patient needs, provide guidance for patients and caregivers, and ultimately maximize outcomes for patients with diabetes in the palliative care setting.
Introduction
Current data from the Centers for Disease Control (CDC) suggest that 23.6 million people in the US over the age of 20 have diabetes. For people over the age of 60, the prevalence of diabetes is estimated at 12.2 million, or 23% of that population. 1 As patients approach EOL, the prevalence of multiple comorbidities increases, thereby increasing the likelihood that practitioners will encounter the dilemma of diabetes management in patients with advanced disease.
Current goals of therapy for patients with diabetes in the general population use hemoglobin A1C with a goal of less than 7 percent. This goal is associated with a significant reduction in long-term microvascular complications; however, the data comes from a general patient-with-diabetes population and may not be translatable to the end-of-life patient population.2–4
In patients with advanced life-limiting diseases, as seen by practitioners of hospice and palliative medicine, it is unclear whether tight glycemic control will demonstrate improved outcomes. In fact, tight glycemic control as patients advance throughout the stages of illness may be associated with increased morbidity. 5 This morbidity often manifests itself as typical symptoms of hypoglycemia, including diaphoresis, anxiety, tremors, weakness, palpitations, and, in extreme situations, seizure. At some point in the care of the palliative medicine patient, practitioners must shift their focus from prevention of long-term complications to patient comfort and individualized goals of care.
The Approach
Empiric evidence for the management of diabetes as a comorbidity in advanced disease remains fragmented; however, there is an approach to use with such patients, in the hope of maximizing patient outcomes and properly addressing individual needs. A firm knowledge of the pathophysiology behind diabetes and glucose homeostasis is of paramount importance for developing an appropriate plan of action.
As happens in the care of many patients with life-limiting disease, a prognosis-based system of triage helps guide decision-making. Patients can be categorized into one of three groups (Table 1):
Management of patients from each of the groups group is unique and requires an individualized approach and care plan.
Managing the Stable Patient with Advanced Disease
Management of the patient with both advanced disease and diabetes can present a number of challenges. Often, this is the longest of the three stages above. Patients in this category may continue to feel as they have for the past several months, due to the insidious nature of their disease.
These patients are inclined to simply continue with their previous regimen, out of deference to their previous training about the importance of glycemic control. Practitioners must use this stage to begin a dialog with patients and caregivers about reducing the intensity of glycemic control. Instruction should focus on the acute prevention of hypoglycemia and maintenance of reasonable prevention of hyperglycemia with levels less than the renal threshold of glucose, which is generally agreed to be around 180mg/dL. There is very little role for A1C in these patients. Patients should be warned of the signs of hypoglycemia, but with the understanding that hypoglycemia unawareness occurs more frequently in the elderly and those with multiple co-morbidities. 6
The acute risks of hyperglycemia, as experienced in this stage, center mainly on the presence of the hyperosmolar state and associated complications, such as osmotic diuresis, recurrent infection, and poor wound healing.
Type I patients with diabetes will continue to require insulin at this stage of their illness. Caution should be used when using long-acting insulin (NPH), due to the risk of prolonged hypoglycemia from its pharmacodynamic peak. In some cases, a dosage adjustment may be necessary. Rapid-acting insulin may be considered a safer alternative to ensure the patient is tolerating food, as this injection can be administered even after a meal has begun,. 7
Often, Type I or Type II patients with diabetes can be instructed at this stage to continue with diabetes medications without change if they have demonstrated the ability to look for specific warning signs. If patients are not eating, or have nausea or vomiting, they should be instructed specifically on how to cut back their dosing. Medication dosing should be decreased in patients with worsening renal disease, given the failure to clear insulin. The presence of liver failure should, similarly, prompt the practitioner to cut back on dosing, given the failure of gluconeogenesis and the poor glycogen stores of the liver (Table 2). Patients who are losing weight should, equally, be prompted to discuss how to reduce their medications with their practitioners, as the risk of hypoglycemia will increase.
Mainly, a pleasure-based diet is prescribed to these patients, with a limit on highly concentrated carbohydrates. Finger-stick glucose tests should be used in only specific situations in Type II patients with diabetes, and Type I patients should likely continue their measurements if they are able.
Managing the Patient with Advancing Underlying Disease and Organ Failure
As patients move into this phase, the importance of glycemic control is less apparent and preventing hypoglycemia is of greater significance. Here, also, patient and caregiver education is of vital importance to prevent inappropriate action. The telltale signs of dehydration and hypoglycemia should be discussed, and an appropriate plan of action should be followed if these complications are encountered.
Type I patients with diabetes often have to decrease their insulin administration at this stage. Often, the presence of renal or hepatic failure becomes more evident at this stage and, for reasons listed above, insulin dosages must be reduced to prevent hypoglycemia.
Similarly, Type II patients with diabetes will also have to decrease their anti-diabetic regimens at this stage. Insulin and sulfonylurea agents should be decreased, given the risk of hypoglycemia if patients demonstrate poor calorie intake. If the presence of renal or hepatic failure is suspected, many oral hypoglycemic dosages must be discontinued or attenuated here as well. The DPP4 inhibitors and any other potentially nauseagenic medications should likely be purged from the patient's regimen. Table 2 provides a full description of the specific medications to address in the presence of organ failure.
In addition to addressing medication administration, the practitioner should be prompted by worsening anorexia and cachexia to fully liberalize patient diets to the extent that their underlying disease will tolerate.
Finger-stick glucose checks are generally eliminated in Type II patients with diabetes and used only where a decision needs to be made for management in Type I patients with diabetes. Some patients and/or caretakers may find abandoning glucose monitoring to be distressing as either a marker of severity of underlying disease and life expectancy or loss of locus of control. This topic should act as a springboard for further discussion about goals of care and prognosis where appropriate.
Diabetes Management in the Actively Dying Patient
As in the previous two stages, a consensus on management is lacking for this stage. Most practitioners in this case would simply withdraw all oral hypoglycemics and stop insulin in most cases of Type I and Type II patients with diabetes.
At this point, care is focused on patient comfort and preparatory bereavement counseling for caretakers and patients, where appropriate.
Specific Medication Considerations (Table 2)
Insulin
Insulins are characterized and administered based on their pharmacodynamic actions. While effective in maintaining glucose control, they are limited by side effects, such as hypoglycemia and weight gain. When a Type I patient with diabetes continues to require insulin, the use of a rapid-acting analog (aspart, glulisine, and lispro) is advantageous to someone who has erratic appetites and meal schedules. They can be administered, based on meal-carbohydrate content, even after the patient starts a meal. In a Type I or Type II diabetes patient, a long-acting insulin analog (glargine or detemir), has the advantage of a virtually “peakless” pharmacodynamic profile, which offers an advantage over NPH insulins. The response should be monitored and dose adjusted as needed. 7 Long-acting insulins are adjusted based on fasting blood glucose.
Sulfonylureas
Sulfonylureas are generally effective, well-tolerated, and inexpensive, however, the duration of action and mode of metabolism make them precarious to use in palliative care patients. Sulfonylureas such as chlorpropamide and glyburide have long half-lives and are metabolized by the liver, which confers a high risk of hypoglycemia in this population. Glipizide, a short-acting sulfonylurea, which metabolizes to an inactive metabolite, or glimepiride, a sulfonyurea with dual renal/hepatic clearance, may be considered safer, due to potential lower incidences of hypoglycemia, although caution should still be taken.
Meglitinides
Repaglinide and nateglinide stimulate the pancreas to secrete insulin in a more rapid and shorter duration than sulfonylureas. These agents can be useful in patients with erratic appetites or those who miss multiple meals – they can be given at the first bite of each meal and withheld if the patient skips a meal. Because of their shorter duration of action, these items have a lower risk of hypoglycemia. 8
Biguanides
Metformin is being widely used to treat Type II diabetes and is quite effective, without producing significant hypoglycemia. Gastrointestinal discomfort can occur in up to 30% of patients and can be managed with appropriate food intake. In patients who already have sporadic appetites and unwanted weight loss, metformin may be undesirable. In addition, a rare but serious side effect of lactic acidosis prohibits the use of metformin in patients with compromised liver or renal function.
Thiazolidinediones
Pioglitazone and rosiglitazone are used as second- or third-line oral agents in the treatment of Type II diabetes. These agents can cause considerable weight gain, mostly from fluid retention and edema. Rosiglitazone has also come under scrutiny as the cause of worsening heart failure, myocardial infarction, and death.
Alpha-glucosidase inhibitors
Acarbose and miglitol reduce the rate of carbohydrate digestion, thereby reducing post-prandial hyperglycemia. They do not cause hypoglycemia when used as monotherapy; however, they produce an unacceptably high incidence of GI distress (flatulence and diarrhea). Reports of liver dysfunction have been documented.
Newer therapies
There is limited data on long-term outcomes of GLP-1 analog (exenatide), amylin analog (pramlintide), and the Di-peptidylpeptidase-IV inhibitor (sitagliptin), which are associated with a significant incidence of nausea. They have the potential to cause hypoglycemia and, more recently, exenatide and sitagliptin have been associated with cases of acute pancreatitis and renal failure, making these agents less desirable for the end-of-life patient. 9
The Use of Steroids in Patients with Diabetes
Corticosteroids, such as dexamethasone or prednisone, are commonly administered to the palliative care patient. This drug class has the tendency to unmask preexisting diabetes or cause diabetes in certain patient populations. Several mechanisms have been proposed, ranging from increased hepatic glucose production to decreasing tissue responsiveness to insulin. The onset of hyperglycemia varies and can occur as soon as a few hours after dosing to months or years for someone on chronic therapy. The effect is generally considered dose-dependent and clinicians should use the lowest effective dose for an individual patient.
It is important for the prescribing clinician to be aware of the hyperglycemic effects of corticosteroids, and anticipate the need to add or modify existing hyperglycemic therapy. 10 The presence of diabetes Type I or II is not an absolute contraindication for prescribing corticosteroids. Rather, practitioners should address the need for such medications based on patient comfort and goals of care. It is possible that corticosteroid administration may precipitate the need to increase anti-diabetic therapy, especially in patients with Type II diabetes.
Conclusion
In conclusion, hospice and palliative medicine practitioners can expect to frequently encounter diabetes and associated complications as comorbidities in end-of-life patients. The medical literature offers little guidance, and is limited, on appropriately managing these complications. Understanding the pathophysiology of diabetes and having a thorough knowledge of the medications appropriate for use in the end-of-life patient with diabetes should act as a framework for discussions with patients and caregivers and in formulating an appropriate plan of care.
Footnotes
Acknowledgments
The authors would like to acknowledge the support of the Cooper Foundation and Dr. Edward Viner, whose generous support has allowed us to write this manuscript.
Author Disclosure Statement
No competing financial interests exist.