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 physiological postprandial concentrations of amylin in subjects without diabetes.11 After a single subcutaneous injection of pramlintide, plasma concentrations 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 pramlintide 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. (A 50% reduction in (P < 0.05) compared to a reduction Getting Started With Pramlintide mealtime insulin is recommended of 0.1% in the placebo group. On Pramlintide is a subcutaneous injec- in the prescribing information for average, pramlintide patients lost tion given within 15 minutes before pramlintide.) 1.1 kg (P < 0.05) in body weight, as the subsequent meal (or snack) that • Pramlintide does not cause opposed to a 0.6 kg weight gain in contains at least 250 kcal or 30 g of hypoglycemia. Because pram- the placebo group. In patients with carbohydrate.8 When adding pramlintide is indicated for use with type 2 diabetes with a baseline A1C lintide to the diabetes treatment mealtime insulin, the risk for of ~9.1%, treatment with 120 μg plan, a number of specific strategies insulin-induced hypoglycemia pramlintide along with mealtime may be helpful. Patients with diabe- may increase. If insulin-induced hypoglycemia occurs, appropri- insulin for 6 months led to a signifi- tes are usually most willing to make ate treatment should be promptly cant reduction of 0.6% (P < 0.05) changes when they understand the instituted. in A1C and average weight loss of impact that those changes will have • Pramlintide does not alter the 1.5 kg (P < 0.05) of body weight, as on their diabetes management, as counterregulatory hormonal opposed to a 0.2% drop in A1C and well as on their overall health.27 response in the presence of a 0.2 kg average weight gain in the Because improvement in insulin-induced hypoglycemia.8,28 placebo group.8,21,22 postprandial blood glucose concen- Finally, pramlintide administered trations is a treatment goal, it may be Consideration of the time action before a meal has been shown to helpful before initiating pramlintide profile of mealtime insulin therapy significantly decrease total caloric therapy to ask patients to perform is crucial to success when adding intake and increase postprandial SMBG just before and 1–2 hours pramlintide. Timing and adjust- satiety relative to placebo treatment. after a meal. This can provide a clear ments in mealtime insulin doses In a randomized, double-blind, picture of their current pre- and should be based on evaluation of placebo-controlled crossover study, postprandial glycemic status. patients’ caloric (primarily carbo- 11 insulin-treated men with type 2 Initiate the first dose of pramlint- hydrate) intake and blood glucose diabetes underwent two standard- ide before the evening meal, which measurements. During initiation of ized meal tests. After an overnight is typically the largest meal of the pramlintide therapy, ongoing clinical fast, a single subcutaneous dose of day and occurs at a time when many judgment is necessary to modify the pramlintide, 120 μg, or placebo was patients are at home and better able treatment plan to best meet indi- administered. After 1 hour, an ad to deal with the potential occur- vidual patients’ blood glucose goals libitum buffet meal was eaten, and rence of nausea. Also, starting with in the safest possible manner. total energy, macronutrient intake, just one dose can help determine the Finally, encourage patients to and meal duration were measured. mealtime insulin adjustment that continue to monitor pre- and post- Hunger ratings and concentrations of works best when adding pramlintide meal blood glucose to assist them in other anorexigenic gut peptides were to the plan. This information can be fine-tuning therapy and help them also analyzed. Compared to placebo, applied as subsequent injections are recognize the benefit of adherence to pramlintide reduced energy intake by added. the treatment plan. 126 Diabetes Spectrum Volume 23, Number 2, 2010 Pharmacy and Therapeutics

glucose control while reducing the incidence of nausea. Adding pramlintide to insulin may carry the risk of insulin-induced hypoglycemia, particularly in patients with type 1 diabetes. In clinical studies of pramlintide, the event rate for severe hypoglycemia was greater in patients with type 1 than in those with type 2 diabetes, which is similar to the risk of severe hypoglycemia in the absence of pramlintide. Combined data from the pivotal placebo-controlled trials in which mealtime insulin was not proactively reduced demonstrated an increased incidence of severe hypoglycemia during the first 3 months of pramlintide treatment (versus placebo) in patients with type 1 diabetes (0.50 vs. 0.19 events/patient- year) and type 2 diabetes (0.09 vs. 0.06 events/patient-year). Severe hypoglycemia was defined as requiring medical assistance. It is notable that in the subsequent 3 months of pramlintide therapy, the risk of insulin-induced severe hypoglycemia was comparable to placebo (pramlintide treatment vs. placebo in type 1 diabetes at 0.27 vs. 0.24 events/ patient-year and in type 2 diabetes at 0.02 vs. 0.07 events/patient-year, respectively).21,22 Figure 3. Pramlintide initiation. Reduce prandial rapid-acting or short-acting In later clinical practice stud- insulin dosages, including fixed-mix insulins (70/30 pre-mixed products) by ies, in which both dose titration of 50%.8 In addition, see the important safety information, including the boxed pramlintide and a proactive prandial warning regarding insulin-induced severe hypoglycemia and appropriate insulin reduction of 30–50% were patient selection criteria, in the product prescribing information. undertaken, a lower event rate of Managing Potential Side Effects of nausea was 47% for pramlintide severe hypoglycemia was reported In clinical trials, there were no compared to 22% for those receiv- compared to the earlier studies that pramlintide-induced changes in vital ing placebo.23 Rates for patients with did not reduce mealtime insulin at signs, abnormal findings on physical type 2 diabetes were less frequent the initiation of pramlintide therapy, 29–31 examination, or clinically relevant and ranged from 15 to 27% (depend- particularly in type 1 diabetes. changes in laboratory tests, including ing on dose) versus 17% for those At the end of 6 months, the overall lipid levels. In addition, no changes assigned to placebo.24 average reduction of prandial insulin in cardiac function or clinically rel- In patients who experience in the clinical practice studies was ~ 10% in patients with type 2 diabe- evant changes in electrocardiograms transient nausea, the nausea usually occurred.21−24 tes and 22% in patients with type 1 subsides after 4–8 weeks of therapy.7 Other than hypoglycemia, the diabetes.29 These data support clinical experi- most frequently reported event with Accordingly, to mitigate the risk pramlintide was nausea. Reports ence that nausea may be managed of insulin-induced hypoglycemia, of nausea were more frequent in by gradual dose titration when titration of pramlintide at initiation, patients with type 1 than in those introducing pramlintide, particularly along with careful glucose monitor- with type 2 diabetes, tended to occur in patients with type 1 diabetes. ing and reduction of the prandial in the early weeks of therapy, were In insulin-sensitive patients with insulin dose, is advised unless mild to moderate in intensity, were type 1 diabetes, clinical experience patients persistently have preprandial dose-dependent, and resolved over commonly finds that titrating pram- glucose concentrations > 250 mg/dl, time.21–24 In patients with type 1 lintide to a dose of 15–30 μg may be in which case smaller reductions (or diabetes, the reported occurrence sufficient to improve postprandial no reduction) may be appropriate.32 Diabetes Spectrum Volume 23, Number 2, 2010 127 Pharmacy and Therapeutics

g g g

Lispro Insulin: Type 2 Diabetes Lispro Insulin: Type 1 Diabetes Regular Insulin: Type 1 Diabetes

300 300 300

250 250 250

200 200 200

150 150 150

Plasma Glucose 100 Plasma Glucose 100 Plasma Glucose 100 0 50 100 150 200 250 0 50 100 150 200 250 0 50 100 150 200 250 Time Relative to Meal (min) Time Relative to Meal (min) Time Relative to Meal (min)

Insulin Lispro Insulin Lispro Regular Insulin Pramlintide 120 µg + Insulin Lispro Pramlintide 60 µg + Insulin Lispro Pramlintide 60 µg + Regular Insulin

Figure 4. Postprandial plasma glucose (mean ± SE) in patients receiving respective mealtime insulin and pramlintide. Adapted from Refs. 32 and 40. A study comparing the effects must be converted to units to dose and resume the prescribed of pramlintide administered with assure the proper dose (Figure 5).8 dose with the following meal. either regular insulin or insulin • A 60-μg pen is available and Patients should never double the lispro demonstrated that pramlintide graduated in recommended doses dose of pramlintide.8 reduced the postprandial glucose for type 1 diabetes, as shown in • If pramlintide therapy is dis- excursion with both types of insulin Figure 3.8 continued for any reason (e.g., (Figure 4).32 Notably, the postpran- • A 120-μg pen is available and surgery or illness), the same initia- dial glucose concentration profile graduated in recommended doses tion protocol should be followed reflected the onset and duration of for type 2 diabetes, as shown in when therapy is resumed.8 8 action of the respective mealtime Figure 3. • A study conducted in patients insulin. Although the effect of delay- • Pramlintide and insulin should with type 1 diabetes using insulin ing the dose of insulin lispro until never be mixed or administered pump therapy along with pram- after the meal was not evaluated using the same syringe. lintide found that a minimal in this trial, this regimen has the • Pramlintide and insulin injection reduction in mealtime insulin was potential to provide a more desir- sites should be separated by at needed when using an extended able postprandial glucose profile least 2 inches. bolus, under physician supervi- • The abdomen or thighs are 35 when used with pramlintide. Insulin sion, to deliver the insulin. approved injection sites for opti- lispro is indicated for use within 15 • To minimize nausea, patients can mal absorption. minutes before or immediately after try avoiding both higher-fat foods • When not in use, pramlintide the respective meal.33 and lying down after eating and should be refrigerated between 36 paying attention to feelings of Patient Education and 46°F, stored away from light, fullness as a cue to stop eating. Diabetes self-management educa- and not used beyond the expira- tion date stamped on the carton. tion is a crucial element of care A comprehensive diabetes educa- • After first use, store pramlintide for all people with diabetes and is tion program should also inform at room temperature or keep at a necessary to improve patient out- patients about self-management temperature not greater than 86°F comes.34 Patients using pramlintide practices to enhance success with any and discard after 30 days. 34 should receive ongoing care under medication therapy. Those include, • Pramlintide is a Category C but are not limited to, SMBG, the guidance of a health care profes- drug and should not be used sional skilled in the use of insulin meal planning, physical activity, in pregnancy unless the physi- recognition and management of and supported by the services of a cian (prescriber) recommends diabetes educator.8 Following are key otherwise based on individual Dose Units messages that should be included in situations. the patient education process when • If nausea occurs with pramlintide 15 μg 2.5 U adding pramlintide therapy to the use, it tends to be mild to moder- 30 μg 5 U diabetes treatment plan. ate and transient and dissipates 45 μg 7.5 U • Pramlintide is a subcutaneous over time. injection available in both pen • Patients should contact their 60 μg 10 U and vial formats. diabetes care provider if nausea is 120 μg 20 U • When using a vial, the approved persistent or severe. delivery method is with a U-100 • If a dose of pramlintide is missed, Figure 5. Conversion of pramlintide insulin syringe, and micrograms patients should omit the missed dose to insulin unit equivalents.8 128 Diabetes Spectrum Volume 23, Number 2, 2010 Pharmacy and Therapeutics

hypoglycemia and hyperglycemia, monal therapeutic approach for pharmacology of pramlintide in the rat: com- and assessment of diabetes-related managing diabetes in those patients parisons with human and rat Amylin. Drug Dev Res 37:231–248, 1996 complications. In addition, it is who are prescribed prandial insulin equally important to provide training therapy. Through the three mecha- 11Weyer C, Maggs DG, Young AA, Kolterman OG: Amylin replacement with specific to troubleshooting special nisms of decreasing food intake, pramlintide as an adjunct to insulin therapy situations, such as illness or stress, slowing the rate of gastric emptying, in type 1 and type 2 diabetes mellitus: a inadequate or omission of insulin and reducing postprandial gluca- physiological approach toward improved dose, inadvertent administration gon release in a glucose-dependent metabolic control. Curr Pharm Des 7:1353– of increased insulin or pramlintide manner, pramlintide helps reduce the 1373, 2001 doses, inadequate food intake, or rate of glucose entry into the blood- 12Vella A, Lee JS, Camilleri M, Szarka LA, missed meals.8,34 stream to better match the ability of Burton DD, Zinsmeister AR, Rizza RA, Klein PD: Effects of pramlintide, an amylin Because pramlintide has the insulin to dispose of blood glucose in analogue, on gastric emptying in type 1 and potential to delay the absorption of the postprandial state.38 In addition type 2 diabetes mellitus. Neurogastroenterol concomitantly administered oral to improvement in A1C, the use of Motil 14:123−131, 2002 medications, when the rapid onset pramlintide typically yields positive 13Samsom M, Szarka LA, Camilleri M, Vella of a concomitant orally adminis- effects on body weight, providing A, Zinsmeister AR, Rizza RA: Pramlinitide, tered agent is a crucial determinant a more physiological approach for an amylin analog, selectively delays gastric of effectiveness (such as analgesics), emptying: potential role of vagal inhibition. glycemic management in people with Am J Physiol 278:G946−G951, 2000 patients should be counseled to type 1 or type 2 diabetes who use take the agent at least 1 hour before 14Fineman MS, Koda JE, Shen LZ, Strobel mealtime insulin. SA, Maggs DG, Weyer C, Kolterman OG: or 2 hours after their pramlintide The human amylin analog, pramlintide, injection. Because of pramlintide’s corrects postprandial hyperglucagonemia in effect on gastric emptying, patients References patients with type 1 diabetes. Metabolism taking drugs that alter gastrointes- 1American Diabetes Association: American 51:636–641, 2002 tinal motility (e.g., anticholinergic Diabetes Month November 2009 [article 15Fineman M, Weyer C, Maggs DG, Strobel online]. Available from http://www.diabetes. S, Kolterman OG: The human amylin analog, agents such as atropine) and agents org/assets/pdfs/adm-fact-sheet.pdf. Accessed that slow the intestinal absorption pramlintide, reduces postprandial hyperglu- 30 March 2010 cagonemia in patients with type 2 diabetes. of nutrients (e.g., alpha-glucosidase 2Kitabchi AE, Umpierrez GE, Murphy MB, Horm Metab Res 34:504–508, 2002 inhibitors) are not candidates for this Kreisberg RA: Hyperglycemic crises in adult 16 8 Nyholm B, Orskov L, Hove K, Gravholt drug. patients with diabetes: a consensus statement CH, Moller N, George K, Alberti MM, from the American Diabetes Association. Moyses C, Kolterman O, Schmitz O: The Monitoring Success Diabetes Care 29:2739–2748, 2006 amylin analog pramlintide improves glycemic After patients have been properly 3Resnik HE, Bardsley J, Foster GL, control and reduces postprandial glucagon educated about normal physiology Ratner RE: Achievement of American concentrations in patients with type 1 diabe- and the missing hormones in dia- Diabetes Association Clinical Practice tes mellitus. Metabolism 48:935−941, 1999 betes that are important to optimal Recommendations among U.S. adults with 17Chapman I, Parker B, Doran C, Feinle- diabetes, 1999–2002: the National Health glycemic control and pramlintide has Bisset C, Wishart J, Strobel S, Wang Y, Burns and Nutrition Examination Survey. Diabetes C, Lush C, Weyer C, Horowitz M: Effect been appropriately titrated in con- Care 29:531–537, 2006 of pramlintide on satiety and food intake in junction with suitable adjustments to 4American Diabetes Association: Standards obese subjects and subjects with type 2 diabe- mealtime insulin therapy, appropri- of medical care in diabetes—2010 [Position tes. Diabetologia 48:838–848, 2005 ate patient outcomes might include: Statement]. Diabetes Care 33 (Suppl. 1):S11– 18Schvartz E, Palmer M, Aman J, Horowitz • Diminished daily blood glucose S61, 2010 M, Stridsberg M, Berne C: Physiological fluctuations 5Edelman S, Maier H, Wilhelm K: hypoglycemia slows gastric empty- • Improved postprandial glycemic Pramlintide in the treatment of diabetes mel- ing in normal subjects and patients with litus. Biodrugs 22:375–386, 2008 insulin-dependent diabetes mellitus. control Gastroenterology 113:60–66, 1997 6Edelman S, Weyer C: Unsolved challenges • Additional reductions in A1C 19 with insulin therapy in type 1 and type 2 dia- Unger R: Glucagon physiology and patho- • Potential decrease in caloric physiology. N Engl J Med 285:443–449, intake that may result in weight betes: potential benefit of replacing amylin, a second β-cell hormone. Diabetes Technol 1971 loss Ther 4:175–189, 2002 20Unger R, Orci L: The role of glucagon in the • Reductions in doses of total, 7 endogenous hyperglycemia of diabetes mel- 8 Kruger D, Gatcomb P, Owen S: Clinical short-, and long-acting insulin implications of amylin and amylin deficiency. litus. Ann Rev Med 28:119–130, 1977 • Greater treatment satisfaction Diabetes Educ 25:389–397, 1999 21Ratner RE, Dickey R, Fineman M, Maggs for patients with type 1 or type 2 8Amylin Pharmaceuticals: SYMLIN® pre- DG, Shen L, Strobel SA, Weyer C, Kolterman diabetes compared to their coun- scribing information. San Diego, Calif., 2008 OG: Amylin replacement with pramlintide terparts using mealtime insulin as an adjunct to insulin therapy improved 9Janes S, Gaeta L, Baumont K, Beeley N, long-term glycaemic and weight control in without adjunctive pramlintide Rink T: The selection of pramlintide for clini- type 1 diabetes mellitus: a 1-year, randomized 36,37 therapy cal evaluation [Abstract]. Diabetes 45 (Suppl. controlled trial. Diabet Med 21:1204–1212, 2):235A, 1996 2004 Conclusion 10Young AA, Vine W, Gedulin BR, Pittner 22Hollander PA, Levy P, Fineman MS, Amylin receptor agonism is emerging R, Janes S, Gaeta LSL, Percy A, Moore CX, Maggs DG, Shen LZ, Strobel SA, Weyer C, as part of an integrated neurohor- Koda JE, Rink TJ, Beaumont K: Preclinical Kolterman OG: Pramlintide as an adjunct to Diabetes Spectrum Volume 23, Number 2, 2010 129 Pharmacy and Therapeutics

insulin therapy improved long-term glycemic 30Guthrie R, Karl D, Wang Y: In an open- 39Westermark P, Engström U, Johnson KH, and weight control in patients with type 2 label clinical study pramlintide lowered A1C, Westermark GT, Betsholtz C: Islet amyloid diabetes: a one-year randomized controlled body weight, and insulin use in patients with polypeptide: pinpointing amino acid residues trial. Diabetes Care 26:784–790, 2003 type 1 diabetes failing to achieve glycemic linked to amyloid fibril formation. Proc Natl targets with insulin therapy [Abstract]. 23Whitehouse F, Kruger DF, Fineman M, Acad Sci 87:5036–5040, 1990 Diabetes 54 (Suppl. 1):A118, 2005 Shen L, Ruggles JA, Maggs DG, Weyer C, 40Maggs DG, Fineman M, Kornstein J, Kolterman OG: A randomized study and 31Edelman S, Garg S, Frias J, Maggs D, Wang Burrell T, Schwartz S, Wang Y, Ruggles open-label extension evaluating the long-term Y, Zhang B, Strobel S, Lutz K, Kolterman JA, Kolterman OG, Weyer CL: Pramlintide efficacy of pramlintide as an adjunct to insu- O: A double-blind, placebo-controlled trial reduces postprandial glucose excursions when lin therapy in type 1 diabetes. Diabetes Care assessing pramlintide treatment in the setting added to insulin lispro in subjects with type 25:724–730, 2002 of intensive insulin therapy in type 1 diabetes. 2 diabetes: a dose-timing study. Diabetes Diabetes Care 29:2189–2195, 2006 24Ratner RE, Want LL, Fineman M, Velte Metab Res Rev 20:55–60, 2004 MJ, Ruggles JA, Gottlieb A, Weyer C, 32Weyer C, Gottlieb A, Kim D, Lutz K, Kolterman OG: Adjunctive therapy with the Schwartz S, Gutierrez M, Wang Y, Ruggles amylin analog pramlintide leads to a com- JA, Kolterman OG, Maggs DG: Pramlintide Hisham A. Alrefai, MD, is a clini- bined improvement in glycemic and weight reduces postprandial glucose excursions when cal endocrinologist at Diabetes, control in insulin-treated patients with type added to regular insulin or insulin lispro in Metabolism and Endocrinology in 2 diabetes. Diabetes Technol Ther 4:51–61, subjects with type 1 diabetes. Diabetes Care 2002 26:3074–3079, 2003 Scottsburg, Ind. Kashif A. Latif, MD, is a clinical endocrinologist 25Pi-Sunyer FX: The impact of weight gain on 33Eli Lilly and Co.: Humalogâ prescribing motivation, compliance, and metabolic con- information. Indianapolis, Ind., 2009 at AM Diabetes Center in Bartlett, trol in patients with type 2 diabetes mellitus. 34American Diabetes Association: National Tenn. Laura B. Hieronymus, MSEd, Postgrad Med J 121:94−107, 2009 standards for diabetes self-management APRN, BC-ADM, CDE, is a 26Mitri J, Hamdy O: Diabetes medication education. Diabetes Care 32 (Suppl. 1):S87– m edical�dical information senior spespe-- and body weight. Expert Opin Drug Saf S94, 2007 cialist for Amylin Pharmaceuticals 8:573−584, 2009 35King AB: Minimal reduction in insulin in Lexington, Ky. Cindy R. 27D’Orsie SM: Lancing the barriers to effec- dosage with pramlintide therapy when pre- Weakley, RN, CDE, is a senior tive adult safety education. J Chem Health treatment near-normal glycemia is established medical science liaison for Amylin Saf 14: 10-12, 2007 and square-wave meal bolus is used. Endocr Pract 15:229–233, 2009 Pharmaceuticals in Collierville, 28Amiel SA, Heller SR, Macdonald IA, 36Marrero DM, Crean J, Zhang B: Effect of Tenn. Robert J. Moss, PharmD, is Schwartz SL, Klaff LJ, Ruggles JA, Weyer a senior medical science liaison for C, Kolterman OG, Maggs DG: The effect adjunctive pramlintide treatment on treat- of pramlintide on hormonal, metabolic or ment satisfaction in patients with type 1 Amylin Pharmaceuticals in Miami, symptomatic responses to insulin-induced diabetes. Diabetes Care 30:210–216, 2007 Fla. hypoglycemia in patients with type 1 diabe- 37Rubin RR, Peyrot M: Assessing treatment tes. Diabetes Obes Metab 7:504–516, 2005 satisfaction in patients treated with pram- Note of disclosure: Dr. Alrefai 29Karl D, Philis-Tsimikas A, Darsow T, linitde as an adjunct to insulin therapy. Curr and Dr. Latif are members of the Lorenzi G, Kellmeyer T, Lutz K, Wang Y, Med Res Opin 23:1919–1929, 2007 speaker’s bureau for, and Ms. Frias J: Pramlintide as a adjunct to insulin 38Roth JD, Maier H, Chen S, Roland BL: Hieronymus, Ms. Weakley, and in patients with type 2 diabetes in a clinical Implications of amylin receptor agonism Dr. Moss are employed by Amylin practice setting reduced A1C, postprandial integrated neurohormonal mechanisms glucose excursions, and weight. Diabetes and therapeutic applications. Arch Neurol Pharmaceuticals, Inc., which manu- Technol Ther 9:191–199, 2007 66:306–310, 2009 factures pramlintide.

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