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Pramlintide: Clinical Strategies for Success Hisham A Pharmacy and Therapeutics Pramlintide: Clinical Strategies for Success Hisham A. Alrefai, MD, Kashif A. Latif, MD, Laura B. Hieronymus, MSEd, APRN, BC-ADM, CDE, Cindy R. Weakley, RN, CDE, and Robert J. Moss, PharmD Diabetes is the most common of Table 1. Summary of Glycemic Recommendations for Non-Pregnant endocrine disorders, affecting Adults With Diabetes almost 24 million people in the United States alone.1 The disease A1C < 7.0%* is chronic in nature and character- Preprandial capillary plasma glucose 70–130 mg/dl ized by hyperglycemia, which can result in distressing daily symptoms Peak postprandial† capillary plasma glucose < 180 mg/dl that include fatigue, blurred vision, thirst, and frequent urination. Key concepts in setting glycemic goals: Untreated hyperglycemia may lead • A1C is the primary target for glycemic control. to diabetic ketoacidosis and hyper- • Goals should be individualized based on: osmolar hyperglycemic state, the • Duration of diabetes two most serious acute metabolic • Age/life expectancy complications of diabetes.2 Over • Comorbid conditions time, if inadequately treated, chronic • Known cardiovascular disease or advanced micro- hyperglycemia can contribute to vascular complications complications such as cardiovascu- • Hypoglycemia unawareness lar disease and stroke and can lead • Individual patient considerations to retinopathy, neuropathy, and • More or less stringent glycemic goals may be appropri- nephropathy. ate for individual patients. A primary goal of diabetes ther- • Postprandial glucose may be targeted if A1C goals are apy is to attain and maintain optimal not met despite reaching preprandial glucose goals. glucose control, which can reduce * Referenced to a nondiabetic range of 4.0–6.0% using a the risk of complications. Yet, despite Diabetes Control and Complications Trial–based assay. the best of efforts, many people do † Postprandial glucose measurements should be made 1–2 not reach the recommended glyce- 3 4 hours after the beginning of the meal, generally peak levels mic targets as outlined in Table 1. in patients with diabetes. Pramlintide, an analog of the human Adapted from Ref. 4. hormone amylin, is an effective therapeutic approach that can assist complements the mechanism by In patients with diabetes, it is well patients in achieving optimal glucose which insulin augments its disap- recognized that insulin deficiency, goals. pearance, resulting in glucose either absolute in type 1 diabetes regulation. or relative in type 2 diabetes, is a Amylin the Hormone In the postprandial state, insulin pathophysiological state that con- Amylin is a 37–amino acid pep- works to remove glucose from the tributes to hyperglycemia.4 Because tide neuroendocrine hormone, bloodstream by enhancing uptake in amylin is also secreted by the pan- which is co-secreted, along with the skeletal muscle and adipose and creatic β-cells, when deterioration insulin, by the pancreatic β-cells. peripheral tissue, as well as suppress- or dysfunction of these cells occurs, Physiologically, amylin and insulin ing hepatic glucose production and a decline in amylin (absolute in type concentrations increase several- the release of glucose from the liver. 1 and relative in type 2 diabetes) is fold in response to nutrient intake. Amylin binds to specific receptors present as well.5 Therefore, the bal- Together, insulin and amylin create a within the central nervous system to ance between glucose appearance diurnal profile that can be described modulate appetite and food intake, and disappearance is disrupted, con- as synergistic. The ability of amylin regulate gastric emptying, and tributing to elevated blood glucose to influence the appearance of meal- reduce production of glucagon in a concentrations in the preprandial derived glucose in the bloodstream glucose-dependent manner.5,6 and, more so, in the postprandial 124 Diabetes Spectrum Volume 23, Number 2, 2010 Pharmacy and Therapeutics evaluations have demonstrated that pramlintide doses of between 60 and 120 μg in patients with diabetes result in plasma concentrations of pramlintide that mimic physiologi- cal postprandial concentrations of amylin in subjects without diabetes.11 After a single subcutaneous injection of pramlintide, plasma concentra- tions peak at about 20 minutes and then decline during the next 3 hours. Pramlintide is excreted by the kidneys, with little or no hepatic metabolism. Its plasma half-life is ~ 50 minutes.11 Clinical evaluations of pram- lintide have shown reductions in postprandial glucose concentrations through at least three distinct mecha- Figure 1. Amylin the is deficient in diabetes. Plasma amylin (mean ± SE) in nisms of action, including slowing of patients without diabetes, n = 27; insulin-using (late-stage) type 2 diabetes, n gastric emptying, prevention of the = 12; type 1 diabetes, n = 190. Data from Ref. 7. postprandial rise in plasma gluca- states (Figure 1).7 An analog of the be avoided in patients who have gon, and increased satiety, leading to amylin hormone has been found to experienced severe hypoglycemia in decreased caloric intake and poten- be effective in restoring this balance.5 the past 6 months or who require the tial weight loss.12–17 use of drugs that stimulate gastro- Patients with diabetes often Patient Profile intestinal motility. Pramlintide is exhibit accelerated gastric emptying Pramlintide is approved for use in contraindicated in patients who have compared to healthy individuals.18 the United States and is indicated a known hypersensitivity to this This may be a result of deficient amy- for patients with type 1 or type 2 medication or any of its components, lin secretion in response to meals, diabetes who take mealtime insulin.8 a confirmed diagnosis of gastropare- among other factors. Because gastric Pramlintide can be considered a sis, or hypoglycemia unawareness.8 emptying is a physiological influence logical choice when these individu- for glucose entering the circulation, als, despite efforts with optimized Pramlintide: Mechanism of Action accelerated gastric emptying may insulin treatment, are unable to reach The human hormone amylin is exacerbate postprandial glucose recommended blood glucose targets. insoluble and has a tendency to self- excursions in patients with diabetes. The chances for success are aggregate, which makes it difficult Pramlintide has been shown to slow greater when patients are guided by to use therapeutically. To overcome gastric emptying, controlling the rate experienced health care professionals this, a soluble, non-aggregating, at which nutrients are delivered from who are skilled in the use of insulin. equipotent analog of human amy- the stomach to the small intestine Patients who are not willing to fol- lin, pramlintide, was formulated and, consequently, the rate at which low through with an intensive insulin (Figure 2).9,10 glucose enters the circulation after regimen and recommended self- Subcutaneous mealtime injections meals.12,13 This effect results in a monitoring of blood glucose (SMBG) of pramlintide have been evaluated decreased postprandial glucose or who have an A1C > 9% are not as a method to replace or supple- excursion without altering the net likely candidates for pramlintide ment amylin in diabetic patients absorption of ingested carbohydrate therapy. Pramlintide therapy should requiring insulin. Pharmacokinetic or other nutrients. Human amylin Pramlintide (analog of amylin) A T A A T A TT A Q TT A Q LN L LN L C C R R F V N F V N H H C C S K S Amide K Amide Y S Y L S T F T L A F N P N SS I G P I P G N N N N T T S V N S VN G G Figure 2. Amino acid sequences of human amylin and pramlintide. Adapted from Refs. 10 and 39. Diabetes Spectrum Volume 23, Number 2, 2010 125 Pharmacy and Therapeutics In patients with diabetes, gluca- about 23% without affecting meal Following are key points to con- gon concentrations are abnormally duration. Analyses of hunger and sider when using pramlintide along elevated during the postprandial hormonal analyte profiles provided with mealtime insulin in diabetes period. This inappropriate secre- evidence that pramlintide may exert therapy. tion of glucagon leads to excess a primary satiety effect indepen- • Start with the lowest dose hepatic glucose production and dently of other gut peptides.17 recommended (Figure 3).8 is an important contributor to These three important actions Increase every 3–7 days based on postprandial hyperglycemia.19,20 of pramlintide offer patients with tolerability. Pramlintide administered before a diabetes who have been prescribed • Although maximum doses are 60 meal significantly reduced postpran- mealtime insulin the chance for μg for type 1 and 120 μg for type dial glucagon secretion compared to improved glucose control without 2 diabetes, the maintenance dose placebo in clinical studies of patients subsequent weight gain, and, in some should be based on tolerability with type 1 or type 2 diabetes.14,15 cases, with weight loss by replacing and effect. The efficacy of pramlintide as the “other” β-cell hormone (amylin), • Reduction in mealtime insu- an adjunct to mealtime insulin has which is deficient along with insulin. lin therapy should be based on been demonstrated in both type In contrast, insulin and many of the clinical judgment respective to 1 and type 2 diabetic patients in available oral agents for glycemic specific patients and their glyce- several long-term, double-blind, control are known to have weight mic values. When pramlintide is placebo-controlled trials.17–24 In the gain as an undesirable effect. Weight added, a reduction of up to 50% type 1 diabetic population, after 6 gain can not only disrupt glycemic in mealtime insulin based on months of treatment with pramlint- control, but may also influence moti- patient profile should be con- ide (30 or 60 μg, three to four times vation and adherence to the diabetes sidered and would be indicated daily), the mean reduction in A1C treatment plan.25,26 at the meal when pramlintide is from a baseline of ~8.9% was 0.4% being used.
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