12 - Amylin, Glucagon-Like Peptide-1 Receptor Agonists, and Dipeptidyl Peptidase IV, DPP-IV, Inhibitors as Novel Treatments for Diabetes

Authors: Unger, Jeff

Title: Diabetes Management in the Primary Care Setting, 1st Edition

Copyright 2007 Lippincott Williams & Wilkins

> Table of Contents > 12 - Amylin, Glucagon-Like Peptide-1 Receptor Agonists, and Dipeptidyl Peptidase IV (DPP-IV) Inhibitors as Novel Treatments for Diabetes

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12

Amylin, Glucagon-Like Peptide-1 Receptor Agonists, and Dipeptidyl Peptidase IV (DPP-IV) Inhibitors as Novel Treatments for Diabetes

Take Home Points

  • Noninsulin hormones play a significant role in determining one's ambient glucose concentration.

  • Glucagon-like peptide-1 (GLP-1), glucagon, amylin, and dipeptidyl peptidase IV (DPP-IV) are novel targets for pharmacologic intervention in patients with diabetes.

  • Concerns regarding treatment-emergent hypoglycemia and weight gain are often associated with intensification of one's diabetes regimen.

  • Currently marketed incretin mimetics and amylin analogues can improve glycemic control, reduce A1C levels, and promote weight loss in patients with diabetes.

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Case 1

Mr. Johnson is a 55-year-old man who works as a commercial truck driver. Seven years ago, he was diagnosed as having type 2 diabetes (T2DM). In July 2003, while taking metformin, 850 mg BID, pioglitazone, 45 mg QD, and glyburide, 20 mg QD, his A1C was 7.3%. He was informed by his physician that because of his increasing symptoms (thirst, weight loss, paresthesias, and fatigue), insulin therapy should be initiated. However, the patient refused, citing Department of Transportation Rules in his state forbidding anyone from driving a commercial vehicle while using insulin therapy for diabetes. By May 2005, the patient's A1C had increased to 8.2%. His diabetes-related symptoms worsened as he had 7 to 10 episodes of nocturia daily, erectile dysfunction, and depression. His blood glucose meter downloads revealed that 89% of his readings over a 30-day period were higher than 170 mg per dL.

Still refusing to initiate insulin therapy, the patient was placed on exenatide, 5 g twice daily. (The Department of Transportation has no written policy regarding the use of exenatide by their commercial drivers.) His metformin dose was continued, and the glyburide was reduced to 10 mg daily. Four weeks later, the dose of exenatide was increased to 10 g twice daily. Three months after exenatide was initiated, the patient's blood glucose download revealed that 87% of his numbers were within the target of 70 to 170. His A1C was 6.9%. There were no documented episodes of hypoglycemia, and the patient's symptoms resolved.

Patients with type 1 and type 2 diabetes often struggle to control daily blood glucose fluctuations despite contemporary advances in insulin pharmacology and self blood glucose monitoring. From the patient's perspective, excessive and unpredictable glucose fluctuations are perceived as a failure to time exogenous insulin use successfully with food intake, failure to use the appropriate doses of medications, or simply becoming unmotivated to exercise. Physicians may view one's inability to achieve targeted A1C levels as the result of nonadherence with a prescribed treatment regimen. Are patients overeating? Are they obtaining refills in a timely manner? Are their home blood glucose logs accurate?

The narrow physiologic range between fasting and postprandial glucose levels (70 to 140 mg per dL) in a normoglycemic individual is maintained because of the influences of multiple hormones, including insulin, GLP-1, amylin, and glucagon. Unfortunately, patients with diabetes experience a number of altered hormonal responses in both the fasting and postprandial states, resulting in significant glycemic fluctuations. Patients who are doing their absolute best to manage their hyperglycemia with both behavioral and pharmacologic interventions become frustrated as their glycemic control deteriorates.

Although the glucodynamic effects of noninsulin hormones have been postulated since the 1940s,1 our ability to manage pharmacologically the alterations in glycemic control resulting from deficient GLP-1 and amylin, as well as hyperglucagonemia, have only recently become clinically available. Patients who utilize these novel pharmacologic agents are discovering the benefits of improvement in overall glycemic control with a reduced risk of hypoglycemia and weight gain.

Barriers to Normalizing Glycemia

The evidence-based target for glycemic control is to attain and maintain an A1C level of 6.5% to 7% or less.2,3,4 Patients with type 1 diabetes (T1DM) most often require physiologic insulin replacement therapy to achieve this targeted A1C, whereas patients with T2DM depend on a variety of oral agents and insulin formulations alone or in combinations to improve their hyperglycemia.

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Unfortunately, many patients become innocent bystanders watching helplessly as their glycemic control deteriorates over time.

The United Kingdom Prospective Diabetes Study (UKPDS)5 was designed to show whether early treatment of hyperglycemia in T2DM can reduce morbidity and increase life expectancy. During this study, 4075 patients with newly diagnosed T2DM were enrolled. Intensively managed patients were randomized to treatment with sulfonylurea (glyburide) or chlorpropamide (Diabinese), metformin, or ultralente insulin. If glycemic control became inadequate with one oral agent, another agent was added, and if oral combined therapy failed, insulin alone was started. If necessary, regular insulin could be added to the ultralente insulin. The primary outcome measurements were fasting plasma glucose levels, A1C, weight change, and frequency of hypoglycemia. The clinical outcomes and the evolution of treatments were followed up for 6 years. Conventionally managed patients (those followed up on diet and exercise alone) were not randomized into the intensively managed protocol until their fasting blood glucose levels exceeded 270 mg per dL. This level of glycemic control was not considered excessive in Europe when the study was initiated in 1977. The average A1C at entry into the trial in both the conventional and intensively managed groups was 9.1%.

Glycemic control improved greatly and equally with all treatments, as the mean A1C decreased about 2% after 1 year. However, despite medication adjustments, glycemia worsened over time in both groups. After 6 years, only half the subjects were able to maintain an A1C less than 8%, and only 40% remained on the single treatment initially assigned. This decline in glycemic regulation was found to be directly related to the loss of pancreatic beta-cell function. By the time a patient is initially diagnosed as having T2DM, at least 50% of the beta cell mass has been impaired.5,6 Insulin can no longer be produced and secreted at a rate that can prevent hyperglycemia. The coupling of insulin's reduced pharmacologic action in the skeletal muscles and adipose tissue (insulin resistance), with a reduction in insulin output by the pancreatic beta cells, results in a progressive disease process.

The major contributor to the total A1C in patients with levels less than 8.5% is postprandial hyperglycemia.7 Currently marketed oral agents and even rapid-acting insulin analogues reduce the postprandial glycemic excursions by 50% or less.8 Residual postprandial hyperglycemia contributes to glucose toxicity and limits efforts to reduce A1C from 7% to the normal 4% to 6% range.

Two of the most significant barriers to achieving normal physiologic glycemic control are hypoglycemia and weight gain. Hypoglycemia may occur during treatment with any insulin or oral secretagogue, especially when glycemic control approaches normal limits. Intensively managed T1DM patients in the Diabetes Control and Complications Trial (DCCT) collectively experienced assistance-requiring events on average once every 6 months.9 Similarly, in the UKPDS, major hypoglycemia occurred in 2.3% of insulin-treated patients

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yearly.10 Acute hypoglycemia can cause motor vehicle accidents, altered levels of consciousness, and seizures. The fear of developing hypoglycemia may limit one's willingness to achieve tight glycemic control.11 In addition, patients in whom hypoglycemic unawareness develops are unable to detect the subtle signs associated with having blood glucose levels less than 60 mg per dL, attempting to carry on their usual and customary activities without any indication that they are in harm's way.

When hypoglycemia occurs or is suspected, patients may eat defensively to reverse uncomfortable symptoms such as sweating, palpitations, dizziness, confusion, weakness, and syncope. Defensive eaters tend to consume foods that are high in fat and calorie content, contributing to weight gain. Hypoglycemia is the rate-limiting step in diabetes management. If patients and physicians did not have to worry about treatment-emergent hypoglycemia, the management of both T1DM and T2DM would certainly be simplified and more aggressive.

Intensively managed patients in both the DCCT and UKPDS noted excessive weight gain when compared with the conventionally treated cohorts. In the DCCT, intensively treated patients gained on average 2.1 kg in the first year and 4.8 kg after a mean follow-up period of 6.5 years.12 Patients treated with insulin or sulfonylurea in the UKPDS gained nearly 10 kg over a 10-year period.13 Weight gain with thiazolidinediones can range from 2 to 5 kg.14 The frustration experienced by patients who gain weight despite sincere attempts at behavioral interventions are only enhanced by the negative feedback they encounter at the time of their office visits. So often they are told that they must get a grip on their food intake or change their exercise routines to control their weight gain. Weight gain and improved glycemic control are not mutually exclusive. As such, criticism regarding a patient's inability to manage his or her increases in weight should be minimized.

The persistence of postprandial hyperglycemia, together with hypoglycemia risk and weight gain associated with the intensification of one's treatment regimen, has renewed interest in the physiology of prandial glucose homeostasis. The traditional description of glycemic control focuses on insulin secretion and insulin action. This model is most accurate in the fasting state, when plasma glucose levels are determined by circulating insulin concentrations and hepatic sensitivity to insulin. Glucose uptake in the periphery during fasting occurs primarily in insulin-independent tissues such as the brain. Low levels of circulating insulin have little effect on glucose uptake by the central nervous system (CNS).15 Modest increases in insulin levels can suppress free fatty acid mobilization from adipose tissue. The liver then becomes more insulin sensitive, blocking the secretion of the counterregulatory hormone glycogen.

The postprandial regulation of plasma glucose is more complicated. An ordinary meal contains 50 to 100 g of carbohydrate, or about 10 to 20 times the total amount of circulating plasma glucose. Multiple hormonal influences help tightly regulate postprandial glycemic excursions (Fig. 12-1).

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Figure 12-1 Hormonal Regulation of Postprandial Glucose Homeostasis. Glucose homeostasis in the postabsorptive state is regulated by a compex interplay between several gut and pancreatic islet hormones, including insulin, amylin, glucagon, dipeptidyl peptidase IV (DPP-IV) enzymes, and incretins. These hormones stimulate a cascade of events in response to nutrient intake that decrease the rate of glucose appearance and increase the rate of glucose disappearance. Glucagon-like peptide-1 (GLP-1) secretion from intestinal L cells has multiple glucoregulatory effects, including glucose-dependent insulin secretion, suppression of glucagon secretions, slowing of gastric emptying, and reduction of food intake. (Adapted from Drucker DJ. The glucagon-like peptides. Endocrinology. 2001;142:521 527.)

The Incretin Effect

The insulin concentrations in the peripheral circulation increase very rapidly (by at least two- to threefold) after an oral glucose meal when compared with a similar intravenous bolus of glucose. This substantial increase in insulin concentrations after an oral glucose load is known as the incretin effect. Two gut hormones, glucose-dependent insulinotropic polypeptide (GIP) and GLP-1, have been shown to account for a substantial portion of the incretin effect.1

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Suppression of Glucagon Secretion

Glucagon is a counterregulatory hormone secreted by the pancreatic alpha cells. Under normal conditions, a postprandial increase in glucose concentration is associated with a corresponding reduction in glucagon. As circulating glucose levels decrease, glucagon levels increase, resulting in a 60% increase in hepatic glucose production and output through gluconeogenesis.16 Glucagon secretion is regulated, in part, by endogenous insulin secretion.17 Insulin action results in the storage of glycogen within hepatocytes. Insulin resistance, insulinopenia, or an increase in glucagon will induce the liver to depolymerize glycogen, resulting in a rise in ambient glucose levels.

Neurohormonal Mechanisms

Neurohormonal mechanisms influence the secretion of insulin and glucagon. Simply seeing or smelling food triggers a first-phase insulin release from the beta cells. Glucose sensors in the portal vein transmit information to the CNS, which, via efferent signaling mechanisms, prepares the liver and skeletal muscles for the postprandial state.18 The plasma glucose concentration also influences the rate of gastric emptying. Hyperglycemia slows peristalsis, whereas hypoglycemia speeds gastric emptying.19 Erratic glycemic control can result in unpredictable gastric emptying. This may be problematic for patients using exogenous insulin. For example, if a rapid-acting insulin analogue is administered 15 minutes before food in a patient whose blood glucose level is 300 mg per dL, the peak insulin concentration will occur much sooner than the increase in serum glucose from the gastrointestinal (GI) absorption. That patient may develop hypoglycemia within 1 to 2 hours of eating, but significant postprandial hyperglycemia 4 to 5 hours later as the carbohydrate absorption occurs with no matched insulin action. A patient with a premeal blood glucose of 50 mg per dL may experience significant and prolonged hypoglycemia if a rapid-acting insulin analogue is injected 15 minutes before a meal, because gastric empting is accelerated, yet insulin absorption rates remain unchanged. Three to 4 hours after eating, hypoglycemia might still occur, if one does not make the appropriate dose adjustments in the insulin.

Abnormal Prandial Responses in Patients with Diabetes

As described earlier, a complex integrated process involving increased secretion of insulin, reduced secretion of glucagon, slowing of gastric emptying, and neural regulation of various tissues normally limits the increase in plasma glucose levels after meals. Many components of this prandial response are abnormal in individuals with diabetes or impaired glucose tolerance. Prandial insulin secretion is absent in T1DM and delayed and reduced in T2DM. GLP-1 secretion is impaired in patients with T2DM and absent in T1DM. Glucagon secretion is substantially elevated in the fasting state and not suppressed after

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meals, resulting in a continuous hyperglycemic state. Patients with gastroparesis have delayed gastric emptying, yet early in the course of the disease process, gastric motility may be increased. These metabolic abnormalities, which are not entirely corrected by exogenous insulin,20 will contribute to a failure to regulate postprandial glucose concentrations. Insulin has no effect on glucagon concentration.

Gastrointestinal Peptides Regulate Postprandial Glycemia

Amylin is co-secreted from pancreatic beta cells with insulin in response to a glucose challenge. Once released, amylin reduces glucagon secretion, inhibits gastric emptying, and reduces food intake. In animal models, a continuous amylin infusion results in weight reduction21 by controlling satiety. Plasma levels of endogenous circulating amylin in healthy individuals are lower in the fasting state and increase fourfold after a meal.22 T1DM is an amylin- and insulin-deficient disease, whereas amylin and insulin levels are often elevated in patients with impaired glucose tolerance and T2DM.22

GIP, produced in the enteroendocrine K cells of the duodenum, is secreted in response to a meal and functions as an incretin hormone. The glucose-lowering capability of GIP appears to be much more potent in animal models. In humans with diabetes, GIP receptors in the beta cell appear to be downregulated and desensitized in association with worsening hyperglycemia.23

GLP-1 is an incretin hormone rapidly released by the L cells of the distal ileum and colon as food is being ingested. Enzymatic inactivation by DPP-IV shortens the biologic activity of GLP-1 to less than 2 minutes.24 GLP-1 controls both fasting and postprandial blood glucose concentrations by multiple actions, primarily by stimulating insulin secretion from pancreatic beta cells while inhibiting glucagon secretion. GLP-1 also slows gastric emptying and enhances satiety, thereby reducing food intake. Whereas short-term administration of a GLP-1 agonist limits food intake, long-term subcutaneous infusion of GLP-1 results in weight loss.25 In animal models, GLP-1 promotes expansion of beta-cell mass while inhibiting beta-cell death (apoptosis).26 These beta-cell protective actions have also been observed in human islets cultured in vitro.27

GLP-1 receptors also are present in heart myocytes. Interestingly, short-term administration of GLP-1 improves myocardial contractility in patients after a myocardial infarction or revascularization procedure.28 In addition to pancreatic beta cells, GLP-1 receptors have been identified in the GI tract, lung, CNS, skeletal muscles, and liver.29 The effects of GLP-1 receptor activation in these extrapancreatic tissues are uncertain.

DPP-IV enzymatically degrades both GIP and GLP-1, reducing their active biologic activity to less than 2 minutes. Because of the potent and rapid effect this enzyme has on incretin hormones, pharmacologic inhibition of

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DPP-IV can modify glucose homeostasis. Experimental studies have demonstrated that DPP-IV inhibition can reduce A1C levels and enhance insulin action, while having minimal effect on satiety or weight regulation.30,31,32 Pharmacologic DPP-IV inhibition also improves islet survival and maintains beta-cell mass in animal models.33 Genetic inactivation of the DPP-IV gene in mice improves glucose tolerance, as circulating levels of GIP and GLP-1 increase after glucose loading.34 Rats with mutant DPP-IV genes exhibit resistance to diet-induced obesity.35

The endocrine actions of glucotropic hormones are summarized in Table 12-1.

Noninsulin Pharmacologic Strategies for Improving Glycemic Control

Amylin Replacement Therapy

The use of exogenous amylin and GLP-1 hormones can improve glycemic fluctuations and reduce postprandial glucose excursions, while reducing one's A1C. Because of the neuroendocrine nature of these hormones, many patients will also experience satiety and weight loss. Pharmacologic agents that are currently available and those in development are summarized in Table 12-2.

Pramlintide

Pramlintide (Symlin) is an analogue possessing pharmacodynamic properties similar to those of the native amylin. The addition of pramlintide to exogenous insulin therapy improves long-term glycemic control beyond that obtained with insulin therapy alone and without weight gain or an increased risk of hypoglycemia.36

In clinical trials, the addition of pramlintide to patients with insulin-requiring T1DM and T2DM has been shown to reduce the A1C approximately 0.5% to 1.0% from baseline when compared with placebo.4 Most important, the proportion of patients who are able to achieve the American Diabetes Association (ADA) glycemic target (A1C <7%) was two to three times greater when pramlintide was added to an established insulin regimen.

One of the most frustrating adverse events associated with overall glycemic improvement in patients using insulin therapy is weight gain. Insulin is a natural growth hormone. Exogenous insulin doses are often substantially higher than the amount of insulin produced by a normally functioning pancreas. Theoretically, exogenous insulin may downregulate beta-cell function, further reducing one's ability to produce and secrete amylin hormone. Amylin is a neuroendocrine hormone that binds to the area postrema of the brain and reduces satiety. Patients with T1DM with a body mass index (BMI) greater than 27 kg per m2 lost an average of 1.6 kg over a 26-week period when compared with those taking placebo.37 A 52-week study of T2DM patients using

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120 g twice daily resulted in an average weight reduction of 1.4 kg compared with a 0.7 kg weight gain for the placebo-treated group.38

TABLE 12-1 Endocrine Actions of Glucotropic Hormones

Insulin
  • Binds to receptors throughout the body to help process glucose disposal
  • Inhibits glucagon secretion
  • Signals the liver to stop glucose production
  • Promotes glycogenesis (conversion of glucose into glycogen)
  • Stimulates fat synthesis
  • Promotes storage of triglycerides in the fat cells
  • Promotes protein synthesis in liver and muscle
Glucagon
  • Promotes glycogenolysis (breakdown of glycogen to glucose)
  • Promotes gluconeogenesis (conversion of other nutrients, primarily protein, into glucose)
  • Promotes output of ketone bodies for use by heart muscle and renal cortex as energy sources
Glucagon-like Peptide-1 (GLP-1)
  • Enhances insulin secretion in glucose-dependent fashion
  • Suppresses postprandial glucagon secretion in a glucose-dependent fashion
  • Regulates the rate of gastric emptying
  • Reduces food intake
  • Increases and preserves beta-cell mass
  • Limits beta-cell apoptosis (death)
Glucose-dependent Insulinotropic Polypeptide (GIP)
  • Glucose-reducing effect appears to be more potent in animals than in humans
Amylin
  • Reduces postprandial glucagon secretion, which in turn leads to a reduction in hepatic glucose output
  • Regulates the rate of gastric emptying to control the rate of nutrient delivery to the small intestine for absorption
  • Reduces food intake and enhances satiety
  • Reduces reactive oxygen species (ROS)
Dipeptidyl Peptidase IV (DPP-IV)
  • DPP-IV enzymatically degrades GIP and GLP-1, limiting the time of their active biologic activity to <l2 min.
  • DPP-IV inhibition can reduce A1C levels and enhance the glucose-reducing effect of insulin.
  • DPP-IV inhibition improves islet survival and maintains beta-cell mass in animal models.
  • Inactivation of the DPP-IV gene in mice and rats improves glucose tolerance as GIP and GLP-1 levels increase after glucose loading.
  • Rodents with mutant DPP-IV genes are resistant to diet-induced obesity.

TABLE 12-2 Pharmacologic Incretin Agents

Agent Basis of Enhanced Incretin Action Clinical Development
Incretin Mimetics
Exenatide 53% homology with GLP-1 receptors results in equivalent biologic activity as GLP-1.
Incretin mimetics work by mimicking the effects of naturally occurring incretin hormone.
FDA approved and indicated for T2DM inadequately controlled with metformin alone or in combination with a sulfonylurea
Exenatide LAR Once-weekly injection of exenatide A 15-wk randomized placebocontrolled phase 2 trial demonstrated a 2% reduction in A1C from baseline, a 50 mg/dL reduction in fasting plasma glucose, and a 7-lb weight reduction.
CJC-1131 Incretin analogue bound to endogenous albumin, which extends the half-life of the drug to approximately 10 d Phase 2 studies
Albugon Recombinant GLP-1-albumin protein with prolonged half-life Phase 2 studies
GLP-1 Analogue
Liraglutide 97% homology with GLP-1 receptors, resulting in equivalent biologic activity as GLP-1 Phase 3
DPP-IV Inhibitors
Sitagliptan FDA approved. Indicated to improve glycemic control in T2DM, alone or with metformin or a thiazolidinedione
Vildagliptin A U.S. regulatory decision is expected in the first half of 2007 for vildagliptin as a once-daily oral treatment for patients with T2DM.
DPP-IV, dipeptidyl peptidase IV; FDA, U.S. Food and Drug Administration; GLP-1, glucagon-like peptide-1; T2DM, type 2 diabetes.

The glucose-lowering effects of pramlintide are related to the drug's ability to improve gastric emptying and reduce postmeal glucagon levels. Pramlintide has minimal effect on fasting glucose levels.

Pramlintide is generally well tolerated, the most common side effect being nausea, which occurs in up to 40% of patients using the drug. However, GI symptoms tend to resolve over the first 2 to 4 weeks of therapy. Advising patients to limit their fatty food intake when initiating pramlintide therapy will lessen their nausea considerably. High-fat foods trigger the release of cholestokinin, an intestinal hormone that tends to intensify nausea. Doses must be titrated slowly to minimize nausea.

Pramlintide alone does not cause hypoglycemia. However, when the drug is used as adjunct therapy in patients using mealtime insulin, hypoglycemia can occur, particularly in patients with T1DM. The following steps may be taken to limit treatment-emergent hypoglycemia in patients with T1DM using pramlintide:

  • Reduce the dose of mealtime insulin by 50%.

  • Patients with insulin pumps using a combined immediate and extended-wave bolus might consider reducing their initial bolus by 75% while increasing the extended-wave bolus insulin dose by 25% delivered over a 3-hour period.

  • Patients must be vigilant regarding the possibility of hypoglycemia. Monitoring blood glucose levels 1 to 2 hours after using pramlintide is essential. Patients with hypoglycemic unawareness who are reluctant to perform frequent home blood glucose monitoring (see Chapter 7) may not be acceptable candidates for using pramlintide.

Pramlintide should be initiated in patients with T1DM at 15 g and increased every 3 to 7 days by an additional 15 g until reaching a well-tolerated maintenance dose of 60 g. At this dose, patients should experience no nausea and some degree of appetite suppression. If significant nausea persists at the 45- or 60- g dose level, reduce the dose to 30 g. Patients who are intolerant of pramlintide at 30 g should consider stopping the drug. T2DM patients can initiate therapy at 60 g with an increase to 120 g within 3 to 7 days, depending on their ability to tolerate the drug. Oral agents may be continued at the prepramlintide doses.

Pramlintide is injected by using 0.3-mL, U-100 insulin syringes. Each 2.5-unit increment on the syringe is equivalent to 15 g of pramlintide, as shown in Table 12-3. Table 12-4 summarizes the treatment protocol for using pramlintide.

Patients who are using insulin pump therapy should adjust only their mealtime boluses while taking pramlintide. Basal insulin rates need not be altered. Patients can correct preprandial hyperglycemia, but the insulin

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sensitivity factor should be reduced initially by 50%. For example, if 1 unit of analogue insulin normally reduces glucose levels by 25 mg per dL, with pramlintide, that same dose of insulin may reduce glucose levels by 50 mg per dL.

TABLE 12-3 Pramlintide Dosing for Patients with Type 1 and Type 2 Diabetes

Dosage Prescribed ( g) Increment Using a U-100 Syringe (units)
15 (Initial dose for T1DM) 2.5
30 5
45 7.5
60 (Initial dose for T2DM. Maintenance dose for T1DM) 10
120 (Maintenance dose for T2DM) 20
T1DM, type 1 diabetes; T2DM, type 2 diabetes.

When starting a patient on pramlintide, consider using a flow sheet including written dose-titration instructions, as shown in Figure 12-2.

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Figure 12-2 Titrating Pramlintide and Insulin Flow Sheet.

TABLE 12-4 Administration of Pramlintide to Patients with Type 1 and Type 2 Diabetes

Notes on Pramlintide Dosing for Patients with Type 2 Diabetes
  1. Initiate pramlintide at 60 g immediately before major meals.
  2. Reduce preprandial rapid-acting insulin, including fixed-mix insulins, by 50%.
  3. Monitor blood glucose levels before meals, 2 h after meals, and at bedtime.
  4. Increase dose to 120 g when no nausea has occurred for 3 to 7 days. If nausea occurs at 120 g, reduce dose to 60 g.
  5. Adjust dose of insulin to optimize glycemic control once the target dose of pramlintide (Symlin) is achieved and nausea has stopped. The dose of Symlin may actually be pushed beyond that recommended in the package insert if the patient is not experiencing satiety or nausea. Over time, slowly increase the dose until the patient develops satiety, nausea or has other adverse events such as postprandial hypoglycemia. If doses are gingerly increased to the point of satiety, weight loss will be more prominent.
  6. The physician should be contacted weekly until a target dose of pramlintide (Symlin) is achieved, pramlintide is well tolerated, and blood glucose levels are stable.
Notes on Pramlintide Dosing for Patients with Type 1 Diabetes
  1. Initiate pramlintide at 15 g immediately before major meals.
  2. Reduce preprandial rapid-acting insulin, including fixed-mix insulins, by 50%. Injecting insulin immediately after the meal may reduce the incidence of postprandial hypoglycemia in some patients.
  3. Monitor blood glucose levels before meals, 2 h after meals, and at bedtime.
  4. Increase pramlintide dose to the next increment (30, 45, 60 g) when no nausea has occurred for 3 days. If significant nausea persists at the 45- to 60- g dose, pramlintide should be decreased to 30 g. If the 30- g dose is not tolerated, Symlin should be discontinued.
  5. Adjust dose of insulin to optimize glycemic control once the target dose of pramlintide (Symlin) is achieved and nausea has stopped. The dose of Symlin may actually be pushed beyond that recommended in the package insert if the patient is not experiencing satiety or nausea. Over time, slowly increase the dose until the patient develops satiety, nausea or has other adverse events such as postprandial hypoglycemia. If doses are gingerly increased to the point of satiety, weight loss will be more prominent.
  6. Doctor should be contacted weekly until a target dose of pramlintide is achieved, pramlintide is well tolerated, and blood glucose levels are stable.
Administration of Pramlintide
  1. Inject pramlintide only into the thigh or abdomen.
  2. Rotate sites so that the same site is not being used repeatedly.
  3. Do not inject pramlintide into the same site where insulin is injected.
  4. If pramlintide dose is missed or forgotten, do not give an additional injection.
  5. Do not mix insulin-use syringes with pramlintide-use syringes.
  6. Pramlintide open vials should be used within 28 days. Open vials do not have to be refrigerated. Unopened vials should be refrigerated.

Case 2

Sarah, age 64, has had T1DM for 22 years. She continues to experience significant wide variations in her daily blood glucose readings, despite using insulin-pump therapy. Her frustration mounts as she is unable to reduce her A1C levels to less than 8.2 %. Any attempt at increasing her basal rates or mealtime boluses has been associated with a higher frequency of hypoglycemic events.

As shown further on (Fig. 12-3A), only 40% of her meter-download readings are within the prescribed target range of 70 to 170 mg per dL, whereas 50% exceed 170 mg per dL. Ten percent of the time, the patient is hypoglycemic. (Ideally, patients who achieve 50% of their readings in the target range will be predicted to have an A1C of 7% or less.)

Figure 12-3B shows the overall improvement in glycemic control at the time of her next office visit.

Figure 12-3 Computerized Glucose Downloads for Sarah, Case 2. A: The patient was placed on pramlintide, 15 g TID (injected before eating), with dose titrations occurring every 3 days as tolerated until she achieved a dose of 60 g TID. She was advised to reduce her mealtime bolus by 50% and provide 25% of the total prandial bolus at the time the meal was started, whereas 75% was to be given as an extended bolus over a 3-hour period. Frequent home monitoring was advised to monitor for postprandial hypoglycemia. B: After the initiation of pramlintide, 69% of the patient's glucose readings were within the targeted range. The frequency of hypoglycemic events was reduced by 50%, and the patient checked her blood glucose levels three times as often (68 vs. 208). Her A1C 4 months after pramlintide was started decreased to 6.8 %, her lowest level in 8 years. The reduction in A1C was also associated with a 2.5-kg weight reduction.

Pharmacologic Enhancement of Glucagon-like Peptide-1

Once endogenous GLP-1 is secreted by the L cells of the intestines, the hormone is rapidly inactivated by the DPP-IV enzyme system and cleared by the kidney. This rapid clearance of GLP-1 has presented researchers with a challenge. Continuous subcutaneous infusion of GLP-1 via an insulin pump for 6 weeks39 has resulted in the following significant pooled metabolic effects: (a) reduction in fasting plasma glucose levels by 77 mg per dL, (b) lowering of A1C by 1.3 %, (c) weight loss of 2 to 3 kg, and (d) improved peripheral insulin sensitivity by 77%. These results are physiologically impressive, yet financially prohibitive, as few patients could afford continuous GLP-1 infusion therapy. Pharmacologic enhancement of GLP-1 action has focused on three other strategies: (a) development of a synthetic analogue form of the GLP-1 hormone (known as an incretin mimetic), (b) creation of a GLP-1 agonist having GLP-1 activity without being inactivated by DPP-IV, and (c) use of DPP-IV inhibitors that would prolong the action of endogenous GLP-1 hormone.

Exenatide

Exenatide (Byetta) is a novel GLP-1 incretin mimetic hormone that has been approved for use in poorly controlled T2DM patients using metformin and/or a sulfonylurea. Gila monsters, which are native to the Sonora Desert, harbor a naturally occurring GLP-1 agonist, called exendin-4, in their salivary glands. Although the Gila monster's exendin-4 is only 53% homologous with human GLP-1, the analogue is not rapidly degraded by DPP-IV and has equal affinity to GLP-1 receptor sites. Exenatide is a synthetic form of exendin-4. The physiologic differences between GLP-1 and exenatide are shown in Table 12-5. Because exenatide is not rapidly degraded by DPP-IV, the drug has a half-life of 2.4 hours and is present in the plasma for up to 10 hours,40 allowing twice-daily administration.

Exenatide shares several clinical features with pramlintide. Exenatide slows gastric emptying, suppresses glucagon production, and promotes satiety. Unlike pramlintide, exenatide potentiates nutrient-stimulated insulin secretion from the pancreatic beta cell in a glucose-dependent fashion (Fig. 12-4). This means that exenatide will enhance insulin secretion, thereby reducing blood glucose levels as long as the patient is not becoming hypoglycemic. As blood glucose levels decrease, beta-cell insulin release will diminish, and glucagon levels will increase to protect the patient against hypoglycemia.

Exenatide initially received U.S. Food and Drug Administration (FDA) approval based on clinical trials involving patients using metformin alone or in combination with a sulfonylurea.41,42,43 In December 2006, the FDA amended the indication for exenatide. Exenatide is now indicated as adjunctive therapy to improve glycemic control in patients with T2DM who are taking metformin,

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a sulfonylurea, a TZD, a combination of metformin plus sulfonylurea, or a combination of metformin and a TZD.44 Subjects in the studies were randomized to exenatide, 5 g twice daily for 4 weeks, or placebo, after which further randomization occurred, giving the exenatide cohort either 5 or 10 g BID. The mean reduction in A1C was 0.9%, and weight loss was 1.9 kg. At 2 years, the reduction in A1C was 1.2% from baseline, and weight loss was 5.5 kg in those who continued therapy with exenatide.45 Weight loss appears to continue for as long as patients take exenatide. Metformin-treated patients tend to lose the most weight. In an open label extension trial, 393 patients taking exenatide 10 g for 82 weeks lost on average of 8 to 10 pounds. The weight reduction was steady and continuous as long as the patients remained on the drug.46

TABLE 12-5 Clinical Similarities between Glucagon-like Peptide-1 (GLP-1) and Exenatide

  GLP-1 Exenatide
Increases glucose-dependent insulin secretion + +
Decreases glucagons secretion and hepatic glucose output + +
Regulates gastric output and decreases rate of nutrient absorption + +
Decreases food intake + +
Improves first-phase insulin response. Decreases plasma glucose immediately to near-normal levels + +
Resistant to DPP-IV degradation - +
Duration in plasma after an SQ injection Short Long
DDP-IV, dipeptidyl peptidase IV.

As with pramlintide, initiation of exenatide resulted in at least a doubling of the incidence of nausea compared with placebo. Severe hypoglycemia was uncommon, but mild-to-moderate hypoglycemia increased initially when exenatide was added to a sulfonylurea.41 For this reason, the dose of sulfonylurea should always be reduced by 50% when exenatide is initiated.

Exenatide therapy has been compared with insulin glargine in patients failing to achieve optimal glycemia control with metformin and a sulfonylurea. After 26 weeks of therapy, the mean A1C reduction (1.1%) was comparable in both groups.47 The incidence of GI side effects and the dropout rate were higher in the exenatide-treated patients. However, patients treated with insulin glargine experienced a mean weight gain of 1.8 kg, whereas exenatide-treated subjects had a mean weight loss of 2.3 kg. Rates of reported hypoglycemia were similar in the different treatment groups.47

Figure 12-5 lists the clinical indications and uses for exenatide.

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Figure 12-4 Glucose-dependent Actions of Glucagon-like Peptide-1 (GLP-1) in Patients with Type 2 Diabetes. GLP-1 is glucose dependent in its action. In this patient with type 2 diabetes with hyperglycemia, GLP-1 (line with gray boxes) was administered by intravenous (IV) infusion, and the effects on the change in the patient's blood glucose levels, insulin levels, and glucagon levels were compared with a similar placebo infusion (PBO). Note that the units on the X axis are in millimoles per liter (mmol/L). To convert to mg per dL, simply multiply by 18. As the GLP-1 infusion begins, glucose levels decline, insulin levels increase, and glucagon levels decline in comparison to placebo. However, as the patient's blood glucose normalizes to 5 mmol per L (90 mg per dL), insulin levels decrease and glucagon levels increase to prevent hypoglycemia. Within 240 min of the start of the infusion, all hormone levels have normalized. These related hormonal actions are typical of the glucose-dependent action seen with incretin hormones. Data are expressed as mean SEM. *P < .05. (Used with permission from Nauck MA, Heimesaat MM, Behle K, et al. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab. 2002;87:1239 1246.)

In clinical practice, attention has recently focused on off-label uses of exenatide, including combination therapy with insulin, combination with a thiazolidinedione (TZD), exenatide monotherapy, and use of exenatide for diabetes prevention. Several clinical trials are ongoing and will evaluate the safety and efficacy of these regimens.

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Figure 12-5 Clinical Indications and Use of Exenatide (Byetta).

Case 3

Sixty-two-year-old Patricia has a 25-year history of poorly controlled T1DM. When initially diagnosed as having diabetes, the patient refused to initiate insulin therapy. She eventually found a physician who agreed to give her a single oral agent. Over time, her diabetes worsened, and numerous long-term complications developed, including

  • Diabetic retinopathy with visual loss

  • Diabetic peripheral neuropathic pain

  • Diabetic autonomic neuropathy (cardiomyopathy, gastroparesis, and nocturnal diarrhea)

  • Chronic kidney disease stage 3 [glomerular filtration rate (GFR), 48 mL per minute per 1.73 m2]

  • Anemia (hemoglobin, 9.9 g)

Figure 12-6 In Appropriately Selected Patients, the Off-label Use of Exenatide Plus Insulin May Have a Profound Effect on Glycemic Control. A: Over a 3-week recording period, only 10% of the patient's blood glucose levels were noted to be within the therapeutic range of 70 to 170 mg per dL, despite using an insulin pump with a total daily dose exceeding 175 units. B: After exenatide was initiated on July 24, the patient's blood glucose levels decreased to therapeutic levels in dramatic fashion.

Returning to our practice for the first time in 20 years, the patient was given intensive insulin therapy. However, she had developed significant insulin resistance, and she failed to show improvement in her glycemic control by using more than 175 units of U-100 insulin daily via an insulin pump. Her A1C remained steady at 11.2% as she became more symptomatic because of the increasing hyperglycemia. The patient's home blood glucose meter download is shown in Figure 12-6A.

In a desperate attempt to improve her glycemic control, the patient was started on exenatide, 5 g BID. Immediately her blood glucose levels decreased to the therapeutic range, as shown. After using exenatide, 10 g, for 3 months, her A1C dropped to 7.2%, her total daily dose of insulin was reduced on average by 50%, and she lost 2 kg of weight (Fig. 12-6B).

One can only speculate why the use of exenatide results in weight reduction in patients using exogenous insulin therapy (Fig. 12-7). Exogenous insulin doses required to maintain euglycemia in patients with T2DM are often substantially higher than the amount of insulin produced by a normally functioning pancreas. Exogenous insulin may downregulate beta-cell function, thereby reducing one's ability to produce and secrete both insulin and amylin. As a neuroendocrine hormone, amylin binds to the area postrema of the brain, inducing satiety. Exenatide may upregulate the ability of the beta cell to produce and secrete endogenous insulin and amylin. Not only will hyperglycemia improve, but satiety will be enhanced, and the patient will often begin to lose weight.

The combination of exenatide and pioglitazone has been studied in patients with T2DM.48 Patients using only exenatide had a reduction in fasting plasma glucose levels of 33 mg per dL. Those using exenatide plus pioglitazone, 30 mg, were able to reduce their fasting plasma glucose levels by an average of 72 mg per dL. Insulin levels were higher, glucagon levels were lower, and satiety was enhanced in patients taking exenatide alone and in combination with the TZD. Although preliminary, the study suggests that the thiazolidinedione GLP-1 combinations offer an additional promising treatment approach. One study submitted to the FDA in which exenatide was added to a TZD resulted in 62% of patients achieving an A1C of 7% or lower, compared with only 16% of patients in the comparator arm. The exenatide patients also lost, on average, 3.3 pounds over 16 weeks compared with a 0.4-pound weight reduction in the comparator group.49

Figure 12-5 summarizes the proper use of exenatide. (See Table 12-6, which compares pramlintide and exenatide.)

Other incretin mimetics currently under investigation include exenatide LAR, which can be injected once weekly, and CJC-1131, which has the longest half-life of any of the incretin-like drugs. Subcutaneous injections of CJC-1131 at 6-week intervals has been shown to improve 24-hour mean glucose concentrations.50

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Figure 12-7 Possible Pharmacologic Mechanism for Weight Reduction in Patients Using Exenatide in Combination with Insulin. Speculation exists as to possible mechanisms for exenatide-induced weight reduction observed in patients with type 2 diabetes by using the drug off-label in combination with exogenous insulin. After one consumes a meal, glucagon-like peptide-1 (GLP-1) is secreted by the L cells of the small intestines, which would stimulate the pancreatic beta cells to produce both insulin and amylin. Once secreted, insulin induces glucose disposal in the periphery. Amylin reduces postprandial glucagon levels and binds to the area postrema of the brain, signaling one to stop eating. In patients with type 2 diabetes, GLP-1 is defi cient, but plasma insulin and amylin levels are typically elevated. Patients are insulin and amylin resistant. Exogenous insulin is thought to downregulate pancreatic beta cells, which then reduce their production and secretion of both endogenous insulin and amylin. Exogenous insulin doses exceed the normal levels of circulating plasma insulin, triggering a desire to eat. Insulin receptors are highly concentrated in the CNS, including within the area postrema. As a GLP-1 agonist, exenatide upregulates the beta cells' ability to secrete endogenous insulin and amylin in response to a meal, thereby reducing the patient's dependence on insulin injections. (Based on data from Werther GA, Hogg A, Oldfi eld BJ, et al. Localization and characterization of insulin receptors in rat brain and pituitary gland using in vitro autoradiography and computerized densitometry. Endocrinology. 1987;121:1562 1570.)

Glucagon-like Peptide-1 Analogue

Incretin mimetics, such as exenatide, replicate the biologic activity of GLP-1 by possessing a unique molecule allowing the drug to bind to GLP-1 receptor sites without being rapidly degraded by the DPP-IV enzyme system. Incretin analogues, such as liraglutide, have a chemical structure that is 97% homologous with human GLP-1 and are resistant to DPP-IV degradation. Given as a once-daily injection, liraglutide, 0.75 mg, has a half-life of 11 to 15 hours. Liraglutide decreases glucagon, increases plasma insulin levels, and improves the 24-hour glucose profiles in patients with T2DM after once-daily administration.51 Liraglutide has

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been shown to reduce A1C levels 0.75% from baseline after 12 weeks, similar to the effects of sulfonylureas, but with weight loss rather than weight gain.51 Side effects in clinical trials with liraglutide include nausea, vomiting, dizziness, and diarrhea.

TABLE 12-6 Pharmacologic Differences between Pramlintide and Exenatide

  Pramlintide Exenatide
Drug type Synthetic amylin analogue Incretin mimetic synthetic hormone
Target patients (indications)
  • T1DM with poor glycemic control despite appropriate, individualized insulin management
  • T2DM with poor glycemic control despite appropriate insulin management with or without SFU and/or metformin
  • T2DM with poor glycemic control
  • On metformin
  • On SFU
  • On metformin + SFU
  • On TZD
  • On metformin + TZD
Effect on glucose levels
  • Reduces postprandial glucagon secretion
  • Slows gastric emptying
  • Induces satiety
  • Enhances insulin release in a glucose-dependent fashion
  • Reduces postprandial glucagon secretion in a glucosedependent fashion
  • Slows gastric emptying
  • Induces satiety
  • Restores first-phase insulin response of beta cells
  • Increases beta-cell mass. Protects against beta-cell death
Doses For T2DM
  • 60 120 g TID before mealtime (120 g is most effective dose)
For T1DM
  • 15 60 g TID before mealtime (60 g is most effective dose)
5 10 g injected within 60 min of mealtime
10 g is most effective dose.
Type of injections Syringes and 5-mL vials (with concentration of 0.6 mg/mL). Pens forthcoming 5- and 10- g unit dose pen injectors
Sites for injection Abdomen and leg Arms, abdomen, leg
Shelf life once opened Keep unused vials refrigerated.
   Once opened, drug can be used for 28 days. Vials can be kept at room temperature once opened.
Always keep pens refrigerated.
   Once used, pens last 28 days.
Average wholesale price per month
  • T1DM, $180
  • T2DM, $360
$184 $216
Most common adverse events
  • Nausea (30%). Symptoms usually decrease within 1 wk of drug initiation.
  • Nausea (44%). Symptoms, if present, decrease within first month of using drug.
Drug interactions
  • If oral meds are to be taken with meals, give meds 1 h before mealtime.
  • If oral meds are to be taken with meals, give meds 1 h before mealtime.
  • Meds that must be taken with food should be used during a snack or at a mealtime when exenatide is not being injected.
Blood glucose monitoring
  • Before and 2 h after meals to monitor for possible hypoglycemia. Once stabilized on maintenance dose, monitoring should continue before each dose of insulin is administered and at bedtime.
  • No change in monitoring frequency is necessary.
Hypoglycemia concerns
  • When given with insulin, pramlintide may cause hypoglycemia. When initiating therapy with pramlintide, reduce the mealtime bolus insulin by 50%.
  • Hypoglycemia may be more frequent when exenatide is co-administered in SFU-using patients. Always reduce the dose of the SFU 50% when using exenatide.
Use with insulin
  • Indicated
  • Not indicated, yet off-label use is common. Clinical trials are ongoing.
Use with TZD
  • Not indicated
  • Indicated in combination with a TZD or a TZD + metformin
Meds, medications; SFU, sulfonylurea; T1DM, type 1 diabetes; T2DM, type 2 diabetes; TZD, thiazolidinedione.

Dipeptidyl Peptidase IV Inhibitor

Once GLP-1 is secreted, the hormone is rapidly degraded within 2 minutes by the enzyme DPP-IV. One way to prolong the pharmacologic action of endogenous GLP-1 in patients with T2DM, who are inherently GLP-1 deficient, is to

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use inhibitors of DPP-IV. These drugs improve glycemic control by preventing the rapid degradation of incretin hormones, thereby improving postabsorptive levels of GLP-1 and GIP. One of the DPP-IV inhibitors, sitagliptin, is currently being marketed in the United States as Januvia. A second DPP-IV inhibitor, valdigliptin (Galvus), is pending FDA approval.

The effectiveness of sitagliptin as monotherapy52 or in combination with metformin53 was examined in type 2 diabetic subjects. In a 12-week double-blind, placebo-controlled study, sitagliptin was administered at a dose of 25, 50, or 100 mg once daily, or 50 mg twice daily, to 552 type 2 diabetic patients who were not taking any hypoglycemic medications.52 For patients who were previously on antihyperglycemic medications, there was a drug washout period before the initiation of the study. Mean baseline A1C values for type 2 diabetic patients recruited for the study ranged from 7.6% to 7.8% across the treatment groups.

In comparison to the placebo-treated groups, sitagliptin therapy led to a significant reduction in A1C values, particularly in those patients receiving 100 mg once daily. Fasting plasma glucose increased by 0.2 mg per dL in the placebo-treated group and decreased by 10.7 to 17.0 mg per dL in a dose-dependent manner for the sitagliptin treatment groups. No significant change in body weight was observed with sitagliptin administration.

The effects of vildagliptin on meal-related beta-cell function and insulin sensitivity were examined in patients with T2DM on metformin monotherapy.54 Patients were randomized to either metformin and placebo or metformin and vildagliptin. Standardized meal tests were performed at the initiation of the study and after 12, 24, and 52 weeks to evaluate meal-related beta-cell function. Administration of metformin and vildagliptin for 52 weeks was associated with reduced fasting plasma glucose, enhanced postprandial insulin secretion, and a reduced proinsulin-insulin ratio, compared with baseline values. In contrast, for the metformin-placebo treated groups, fasting plasma glucose increased; postmeal insulin secretion decreased; and no net change was observed for the proinsulin-insulin ratio. The results of this 52-week study demonstrated that meal-related beta-cell function was improved by vildagliptin in metformin-treated patients over 1 year.

Vildagliptin 100 mg per day in combination with pioglitazone 45 mg per day was found to increase the levels of active GLP-1 and reduce postprandial glucose levels by 10% within 12 weeks.55

A 52-week randomized, double-blind study compared vildagliptin 50 mg twice daily (n = 526) with metformin 1,000 mg twice daily (n = 254) in drug-na ve T2DM patients with a mean baseline A1C of 8.7%. The vildagliptin cohort reduced their mean A1C from baseline by 1% in comparison to a 1.4% reduction by those using metformin. However, vildagliptin was better tolerated with a lower incidence of GI side effects than metformin.56

In other clinical trials, vildagliptin appears to have a positive effect on postprandial triglyceride levels,57 blood pressure,58 postprandial glucagon levels,59 and endogenous glucose production.59

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TABLE 12-7 Pharmacologic Actions of Pramlintide, Exenatide, and DPP-IV Inhibitors

  Pramlintide Exenatide DPP-IV Inhibitors
Enhance insulin secretion No Yes Yes
Inhibit glucagon secretion Yes Yes Yes
Slow gastric emptying Yes Yes No
Induce satiety and weight loss Yes Yes No
Improve beta-cell function No Yes Yes
Reference: Riddle MC, Drucker DJ. Emerging therapies mimicking the effects of amylin and glucagon-like peptide 1. Diabetes Care. 2006;29:435 449.

There is considerable interest in the DPP-IV agents for T2DM because, as a class, they appear to be well tolerated and can be used effectively as monotherapy or in combination with other antidiabetic medications. Furthermore, their apparent beneficial effects on beta-cell function raise the possibility that these agents may be able to modify the natural history of T2DM. Although the emerging safety profile of the DPP-IV inhibitors appears to be excellent, the long-term safety of these agents has not yet been ascertained. The DPP-IV inhibitors exhibit promising short-term effects on enhancement of beta-cell function; however, their long-term durability compared with that of other oral antidiabetic agents used in the treatment of T2DM remains unknown.

Primary care physicians may also question which patients to place on a DPP-IV inhibitor. These drugs are certainly more expensive than metformin, do not lower A1C levels more than metformin, and do not result in any appreciable weight loss. One might consider using a DPP-IV soon after the diagnosis of T2DM is made, in a patient with an A1C lower than 8% who is not excessively overweight. Using a DPP-IV inhibitor with a TZD will cost on average $13 per day, which is a large price to pay for a minimum reduction in A1C.60 The pharmacologic actions of pramlintide, exenatide, and the DPP-IV inhibitors are listed in Table 12-7.

Summary

Incretin mimetics are compounds that enhance the glucose-dependent insulin secretion of GLP-1, a naturally occurring hormone released from the L cells of the intestines in response to an oral glucose meal. GLP-1 is deficient in individuals with impaired glucose tolerance and T2DM. As a result, first-phase insulin secretion becomes defective early in the course of glucose intolerance and is generally accepted as the primary marker of pancreatic

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beta-cell death. Three pharmacologic approaches can be used to improve GLP-1 action in individuals with hyperglycemia.

  • Exenatide is a true incretin mimetic drug that is structurally similar to GLP-1 and is able to bind to GLP-1 receptors.

  • DPP-IV inhibitors exert their pharmacologic effect by preventing the enzymatic degradation of GLP-1.

  • GLP-1 analogues are natural compounds that bind directly to GLP-1 receptors. All three agents have diverse mechanisms of action, including the glucose-dependent effect of increased insulin levels in the postmeal state and the ability to reduce postprandial glucagon secretion, which is typically elevated in patients with T2DM. As neuroendocrine hormones, GLP-1 and amylin appear to improve gastric emptying, induce satiety, and promote weight loss. Thus incretin mimetics, incretin analogues, DPP-IV inhibitors, and amylin analogues are technically insulin secretagogues, which favor weight loss rather than weight gain. Incretin mimetics protect and preserve pancreatic beta-cell function while preventing beta-cell death.

As a class, these drugs are well tolerated. The injected drugs cause more nausea and more hypoglycemia in combination with sulfonylureas or insulin than do the DPP-IV inhibitors. The weight loss effect as well as the overall improvement in glycemic control seems to be better maintained with exenatide, which also has been the most clinically studied drug in this class.

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Diabetes Management in the Primary Care
Diabetes Management in Primary Care
ISBN: 0781787629
EAN: 2147483647
Year: 2007
Pages: 19
Authors: Jeff Unger

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