Feature Article/Considering Pramlintide Therapy Considering Pramlintide Therapy for Postprandial Blood Glucose Control Belinda P. Childs, ARNP, MN, BC-ADM, CDE; Nicole C. Kesty, PhD; Eric Klein, MD; Richard Rubin, PhD, CDE; and Allison Wick, MSN, ARNP, CDE Abstract Diabetes is a chronic disease affecting Several therapeutic options are cur- > 20 million Americans, and its inci- rently available to address postprandi- dence, especially in the form of type 2 al glucose fluctuations, including diabetes, is increasing. Multiple thera- rapid-acting insulin analogs, incretin peutics are available that address the mimetics, dipeptidyl peptidase IV dysregulation of the multiple hor- inhibitors, α-glucosidase inhibitors, mones responsible for glucose home- meglitinides, and amylinomimetics. ostasis. Despite the various options, This article presents the experiences of tight glycemic control is often elusive. three patients for whom pramlintide, Additionally, the pursuit of tight an amylinomimetic, was identified as glycemic control is generally accom- an appropriate therapeutic option. panied by various clinical challenges, Practical considerations for clinicians, such as hypoglycemia, weight gain, patient lifestyle factors, and percep- and glucose fluctuations, in particular, tions of pramlintide therapy are also postprandial fluctuations. presented. Diabetes, a chronic disease affecting postprandial hyperglycemia without ~ 20.8 million Americans,1 is character- causing concomitant weight gain, ized by chronic hyperglycemia resulting patients now have additional tools to from the body’s inadequate physiologi- manage their diabetes. cal response to glucose. In type 1 dia- betes, secretion of insulin and amylin Glucose Homeostasis into the circulatory system is absolutely Glucose homeostasis is maintained by deficient because of the destruction of a complex multihormonal system that pancreatic β-cells, whereas in type 2 continuously balances the appearance diabetes, secretion of insulin and and disappearance of glucose. Key amylin is abnormal because of progres- pancreatic and intestinal hormones sive β-cell dysfunction.2–4 In addition to that regulate this system include the physical manifestations of the dis- glucagon, insulin, amylin, and ease, diabetes also carries the risk for glucagon-like peptide-1 (GLP-1).10 development of microvascular and Glucagon, secreted from the pancreat- macrovascular complications.1,5–9 ic α-cells, regulates glucose appearance Patient concerns extend beyond the by signaling the liver to produce and threat of diabetes-related complica- release glucose in the fasting state.10 tions. Daily life is burdened by high Insulin and amylin are cosecreted from and low glucose concentrations, the pancreatic β-cells in response to which require vigilant daily monitor- meals. During the postprandial period, ing, and by the fear of hypoglycemia. insulin suppresses hepatic glucose Management of diet and physical production and facilitates the uptake activity to avoid glucose excursions, of glucose from the circulation into the concerns regarding weight, and a peripheral tissues for use as an energy sense of constant hunger add addi- source,10 thus playing an important tional stress to the daily diabetes rou- role in the disappearance of glucose Address correspondence to Belinda P. tine, leaving many patients feeling from the circulation. Amylin influ- Childs, ARNP, MN, BC-ADM, CDE, inadequate in the management of ences the rate of glucose appearance Mid-America Diabetes Associates, their disease. However, with the into the circulation by three mecha- PA, 200 S. Hillside, Wichita, KS recent introduction of new classes of nisms: suppression of postprandial 67211. therapies that specifically address glucagon secretion, regulation of gastric 108 Diabetes Spectrum Volume 20, Number 2, 2007 Feature Article/Childs et al. emptying, and regulation of appetite interactions of exogenously adminis- ago. She has a history of hyperten- and food intake.11 Postprandial tered insulin, ingested glucose, and sion, dyslipidemia, and obesity. She is glucagon secretion is also suppressed hepatic glucose production can cause a single mother who works an erratic by insulin and GLP-1. GLP-1, secreted wide fluctuations in glucose concen- schedule of day and night shifts as a by intestinal cells in response to meals, trations, resulting in hypoglycemic radiology technician. Initially, Judy enhances glucose-dependent insulin and hyperglycemic excursions. Lack was able to control her diabetes with secretion, suppresses postprandial of glucagon suppression, which results diet and exercise, but after 2 years, glucagon secretion, slows gastric in inappropriate postprandial hepatic other treatment options were needed emptying, and reduces food intake.10 glucose production, and accelerated to maintain glycemic control. The complementary actions of gastric emptying, which contributes to Patients with type 2 diabetes have a insulin and amylin help to maintain rapid, ill-timed intestinal glucose broad choice of therapies, including postprandial glucose homeostasis. In absorption, are major contributors to oral medications, such as biguanides, patients with diabetes, the relative or postprandial hyperglycemia.17 thiazolidinediones, sulfonylureas, absolute deficiency of insulin and meglitinides, and DPP-IV inhibitors, amylin disrupts maintenance of glu- Postprandial Glycemic Control and injectables, such as insulin, amyli- cose homeostasis. Under the influence The American Diabetes Association nomimetics, and incretin mimetics. of glucagon, hepatic glucose produc- recommends a target A1C of < 7.0%.18 These medications address glycemic tion assures adequate glucose concen- A1C is a composite of long-term aver- control through several different trations during the fasting state. In the age fasting and postprandial glucose mechanisms of action (Table 1).The fed state, hepatic glucose production levels. As A1C levels approach 7.0%, biguanides decrease hepatic glucose is not needed. However, in patients the relative contribution of postprandial production, sulfonylureas and megli- with diabetes, glucagon secretion does glucose to overall glycemic control is tinides promote insulin secretion, and not decrease appropriately even when ~ 70%.19 Elevated postprandial glucose thiazolidinediones improve target cell meal-derived glucose is present, fur- concentrations can adversely affect response to insulin, thereby decreasing ther exacerbating the meal-derived mood and cognitive function.20,21 hepatic glucose production and increas- hyperglycemia typical of diabetes. Additionally, recent studies have report- ing glucose uptake.27 Exenatide, an ed that hyperglycemia-induced oxida- incretin mimetic, exhibits many of the Clinical Challenges tive stress may increase the risk of car- actions of GLP-1, whereas DPP-IV Chronic hyperglycemia increases the diovascular disease.22–26 Thus, attention inhibitors slow the degradation of risk of developing microvascular and to postprandial glucose is necessary to GLP-1.28,29 Pramlintide, a soluble macrovascular complications.5,7,8 achieve glycemic targets and reduce risk amylin agonist, exhibits glucoregulato- Patients with diabetes and their health of long-term diabetes complications. ry actions similar to those of amylin.30–34 care providers are encouraged to A number of therapeutic agents When diet and exercise were no achieve tight glycemic control to address postprandial glucose control, longer effective, metformin, a reduce the occurrence of diabetes- including rapid-acting insulins, incretin biguanide, was added to Judy’s treat- related complications. However, pur- mimetics, dipeptidyl peptidase IV (DPP- ment regimen. Over the next few suit of this goal is often accompanied IV) inhibitors, α-glucosidase inhibitors, years, metformin alone was insuffi- by the challenges of preventing hypo- meglitinides, and amylinomimetics. cient in maintaining glycemic control, glycemia, avoiding weight gain associ- The cases that follow describe the and nateglinide, a meglitinide, was ated with treatment of diabetes, and experiences of three patients for whom added. Eventually, the combination of reducing glucose fluctuations, in par- pramlintide, an amylinomimetic, was metformin and nateglinide no longer ticular, postprandial fluctuations. identified as an appropriate therapeutic provided adequate glycemic control, The goal of diabetes therapy is to option. Practical considerations for and basal insulin was added. achieve and maintain near-normal clinicians, patient lifestyle factors, and Patients with type 2 diabetes are glycemia. However, as patients perceptions of pramlintide therapy are often reluctant to start insulin thera- approach normoglycemia, the risk of also presented. py, despite its glycemic benefits. severe hypoglycemia increases.7,12 Because of the increased risk of hypo- Hypoglycemia is often a deterrent to Case Studies glycemia, insulin therapy requires intensive therapy for patients and The cases presented below are intend- more vigilant blood glucose monitor- health care providers and is also prob- ed to provide practical education ing and active dosage adjustments lematic for patients’ significant others. based on the actual clinical experience based on food intake and exercise. Additionally, insulin and many oral of the authors with pramlintide. Because insulin carries the potential agents used to treat diabetes often Insulin adjustment strategies discussed for hypoglycemia and weight gain,7,13 result in weight