Pramlintide: Clinical Strategies for Success

Amylin is a 37–amino acid peptide neuroendocrine hormone, which is co-secreted, along with insulin, by the pancreatic β-cells. Physiologically, amylin and insulin concentrations increase several-fold in response to nutrient intake. Together, insulin and amylin create a diurnal profile that can be described as synergistic. The ability of amylin to influence the appearance of meal-derived glucose in the bloodstream complements the mechanism by which insulin augments its disappearance, resulting in glucose regulation.

In the postprandial state, insulin works to remove glucose from the bloodstream by enhancing uptake in the skeletal muscle and adipose and peripheral tissue, as well as suppressing hepatic glucose production and the release of glucose from the liver. Amylin binds to specific receptors within the central nervous system to modulate appetite and food intake, regulate gastric emptying, and reduce production of glucagon in a glucose-dependent manner.^5,6 

In patients with diabetes, it is well recognized that insulin deficiency, either absolute in type 1 diabetes or relative in type 2 diabetes, is a pathophysiological state that contributes to hyperglycemia.⁴  Because amylin is also secreted by the pancreatic β-cells, when deterioration or dysfunction of these cells occurs, a decline in amylin (absolute in type 1 and relative in type 2 diabetes) is present as well.⁵  Therefore, the balance between glucose appearance and disappearance is disrupted, contributing to elevated blood glucose concentrations in the preprandial and, more so, in the postprandial states (Figure 1).⁷  An analog of the amylin hormone has been found to be effective in restoring this balance.⁵ 

Pramlintide is approved for use in the United States and is indicated for patients with type 1 or type 2 diabetes who take mealtime insulin.⁸  Pramlintide can be considered a logical choice when these individuals, despite efforts with optimized insulin treatment, are unable to reach recommended blood glucose targets.

The chances for success are greater when patients are guided by experienced health care professionals who are skilled in the use of insulin. Patients who are not willing to follow through with an intensive insulin regimen and recommended self-monitoring of blood glucose (SMBG) or who have an A1C > 9% are not likely candidates for pramlintide therapy. Pramlintide therapy should be avoided in patients who have experienced severe hypoglycemia in the past 6 months or who require the use of drugs that stimulate gastrointestinal motility. Pramlintide is contraindicated in patients who have a known hypersensitivity to this medication or any of its components, a confirmed diagnosis of gastroparesis, or hypoglycemia unawareness.⁸ 

The human hormone amylin is insoluble and has a tendency to self-aggregate, which makes it difficult to use therapeutically. To overcome this, a soluble, non-aggregating, equipotent analog of human amylin, pramlintide, was formulated (Figure 2).^9,10 

Subcutaneous mealtime injections of pramlintide have been evaluated as a method to replace or supplement amylin in diabetic patients requiring insulin. Pharmacokinetic 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 mechanisms of action, including slowing of gastric emptying, prevention of the postprandial rise in plasma glucagon, and increased satiety, leading to decreased caloric intake and potential weight loss.^12–17 

Patients with diabetes often exhibit accelerated gastric emptying compared to healthy individuals.¹⁸  This may be a result of deficient amylin secretion in response to meals, among other factors. Because gastric emptying is a physiological influence for glucose entering the circulation, accelerated gastric emptying may exacerbate postprandial glucose excursions in patients with diabetes. Pramlintide has been shown to slow gastric emptying, controlling the rate at which nutrients are delivered from the stomach to the small intestine and, consequently, the rate at which glucose enters the circulation after meals.^12,13  This effect results in a decreased postprandial glucose excursion without altering the net absorption of ingested carbohydrate or other nutrients.

In patients with diabetes, glucagon concentrations are abnormally elevated during the postprandial period. This inappropriate secretion of glucagon leads to excess hepatic glucose production and is an important contributor to postprandial hyperglycemia.^19,20  Pramlintide administered before a meal significantly reduced postprandial glucagon secretion compared to placebo in clinical studies of patients with type 1 or type 2 diabetes.^14,15 

The efficacy of pramlintide as an adjunct to mealtime insulin has been demonstrated in both type 1 and type 2 diabetic patients in several long-term, double-blind, placebo-controlled trials.^17–24  In the type 1 diabetic population, after 6 months of treatment with pramlintide (30 or 60 μg, three to four times daily), the mean reduction in A1C from a baseline of ~8.9% was 0.4% (P < 0.05) compared to a reduction of 0.1% in the placebo group. On average, pramlintide patients lost 1.1 kg (P < 0.05) in body weight, as opposed to a 0.6 kg weight gain in the placebo group. In patients with type 2 diabetes with a baseline A1C of ~9.1%, treatment with 120 μg pramlintide along with mealtime insulin for 6 months led to a significant reduction of 0.6% (P < 0.05) in A1C and average weight loss of 1.5 kg (P < 0.05) of body weight, as opposed to a 0.2% drop in A1C and a 0.2 kg average weight gain in the placebo group.^8,21,22 

Finally, pramlintide administered before a meal has been shown to significantly decrease total caloric intake and increase postprandial satiety relative to placebo treatment. In a randomized, double-blind, placebo-controlled crossover study, 11 insulin-treated men with type 2 diabetes underwent two standardized meal tests. After an overnight fast, a single subcutaneous dose of pramlintide, 120 μg, or placebo was administered. After 1 hour, an ad libitum buffet meal was eaten, and total energy, macronutrient intake, and meal duration were measured. Hunger ratings and concentrations of other anorexigenic gut peptides were also analyzed. Compared to placebo, pramlintide reduced energy intake by about 23% without affecting meal duration. Analyses of hunger and hormonal analyte profiles provided evidence that pramlintide may exert a primary satiety effect independently of other gut peptides.¹⁷ 

These three important actions of pramlintide offer patients with diabetes who have been prescribed mealtime insulin the chance for improved glucose control without subsequent weight gain, and, in some cases, with weight loss by replacing the “other” β-cell hormone (amylin), which is deficient along with insulin. In contrast, insulin and many of the available oral agents for glycemic control are known to have weight gain as an undesirable effect. Weight gain can not only disrupt glycemic control, but may also influence motivation and adherence to the diabetes treatment plan.^25,26 

Pramlintide is a subcutaneous injection given within 15 minutes before the subsequent meal (or snack) that contains at least 250 kcal or 30 g of carbohydrate.⁸  When adding pramlintide to the diabetes treatment plan, a number of specific strategies may be helpful. Patients with diabetes are usually most willing to make changes when they understand the impact that those changes will have on their diabetes management, as well as on their overall health.²⁷ 

Because improvement in postprandial blood glucose concentrations is a treatment goal, it may be helpful before initiating pramlintide therapy to ask patients to perform SMBG just before and 1–2 hours after a meal. This can provide a clear picture of their current pre- and postprandial glycemic status.

Initiate the first dose of pramlintide before the evening meal, which is typically the largest meal of the day and occurs at a time when many patients are at home and better able to deal with the potential occurrence of nausea. Also, starting with just one dose can help determine the mealtime insulin adjustment that works best when adding pramlintide to the plan. This information can be applied as subsequent injections are added.

Following are key points to consider when using pramlintide along with mealtime insulin in diabetes therapy.

• Start with the lowest dose recommended (Figure 3).⁸  Increase every 3–7 days based on tolerability.

• Although maximum doses are 60 μg for type 1 and 120 μg for type 2 diabetes, the maintenance dose should be based on tolerability and effect.

• Reduction in mealtime insulin therapy should be based on clinical judgment respective to specific patients and their glycemic values. When pramlintide is added, a reduction of up to 50% in mealtime insulin based on patient profile should be considered and would be indicated at the meal when pramlintide is being used. (A 50% reduction in mealtime insulin is recommended in the prescribing information for pramlintide.)

• Pramlintide does not cause hypoglycemia. Because pramlintide is indicated for use with mealtime insulin, the risk for insulin-induced hypoglycemia may increase. If insulin-induced hypoglycemia occurs, appropriate treatment should be promptly instituted.

• Pramlintide does not alter the counterregulatory hormonal response in the presence of insulin-induced hypoglycemia.^8,28 

Consideration of the time action profile of mealtime insulin therapy is crucial to success when adding pramlintide. Timing and adjustments in mealtime insulin doses should be based on evaluation of patients' caloric (primarily carbohydrate) intake and blood glucose measurements. During initiation of pramlintide therapy, ongoing clinical judgment is necessary to modify the treatment plan to best meet individual patients' blood glucose goals in the safest possible manner.

Finally, encourage patients to continue to monitor pre- and post-meal blood glucose to assist them in fine-tuning therapy and help them recognize the benefit of adherence to the treatment plan.

In clinical trials, there were no pramlintide-induced changes in vital signs, abnormal findings on physical examination, or clinically relevant changes in laboratory tests, including lipid levels. In addition, no changes in cardiac function or clinically relevant changes in electrocardiograms occurred.^21–24 

Other than hypoglycemia, the most frequently reported event with pramlintide was nausea. Reports of nausea were more frequent in patients with type 1 than in those with type 2 diabetes, tended to occur in the early weeks of therapy, were mild to moderate in intensity, were dose-dependent, and resolved over time.^21–24  In patients with type 1 diabetes, the reported occurrence of nausea was 47% for pramlintide compared to 22% for those receiving placebo.²³  Rates for patients with type 2 diabetes were less frequent and ranged from 15 to 27% (depending on dose) versus 17% for those assigned to placebo.²⁴ 

In patients who experience transient nausea, the nausea usually subsides after 4–8 weeks of therapy.⁷  These data support clinical experience that nausea may be managed by gradual dose titration when introducing pramlintide, particularly in patients with type 1 diabetes. In insulin-sensitive patients with type 1 diabetes, clinical experience commonly finds that titrating pramlintide to a dose of 15–30 μg may be sufficient to improve postprandial 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 

In later clinical practice studies, in which both dose titration of pramlintide and a proactive prandial insulin reduction of 30–50% were undertaken, a lower event rate of severe hypoglycemia was reported compared to the earlier studies that did not reduce mealtime insulin at the initiation of pramlintide therapy, particularly in type 1 diabetes.^29–31  At the end of 6 months, the overall average reduction of prandial insulin in the clinical practice studies was ~ 10% in patients with type 2 diabetes and 22% in patients with type 1 diabetes.²⁹ 

Accordingly, to mitigate the risk of insulin-induced hypoglycemia, titration of pramlintide at initiation, along with careful glucose monitoring and reduction of the prandial insulin dose, is advised unless patients persistently have preprandial glucose concentrations > 250 mg/dl, in which case smaller reductions (or no reduction) may be appropriate.³² 

A study comparing the effects of pramlintide administered with either regular insulin or insulin lispro demonstrated that pramlintide reduced the postprandial glucose excursion with both types of insulin (Figure 4).³²  Notably, the postprandial glucose concentration profile reflected the onset and duration of action of the respective mealtime insulin. Although the effect of delaying the dose of insulin lispro until after the meal was not evaluated in this trial, this regimen has the potential to provide a more desirable postprandial glucose profile when used with pramlintide. Insulin lispro is indicated for use within 15 minutes before or immediately after the respective meal.³³ 

Diabetes self-management education is a crucial element of care for all people with diabetes and is necessary to improve patient outcomes.³⁴  Patients using pramlintide should receive ongoing care under the guidance of a health care professional skilled in the use of insulin and supported by the services of a diabetes educator.⁸  Following are key messages that should be included in the patient education process when adding pramlintide therapy to the diabetes treatment plan.

• Pramlintide is a subcutaneous injection available in both pen and vial formats.

• When using a vial, the approved delivery method is with a U-100 insulin syringe, and micrograms must be converted to units to assure the proper dose (Figure 5).⁸ 

• A 60-μg pen is available and graduated in recommended doses for type 1 diabetes, as shown in Figure 3.⁸ 

• A 120-μg pen is available and graduated in recommended doses for type 2 diabetes, as shown in Figure 3.⁸ 

• Pramlintide and insulin should never be mixed or administered using the same syringe.

• Pramlintide and insulin injection sites should be separated by at least 2 inches.

• The abdomen or thighs are approved injection sites for optimal absorption.

• When not in use, pramlintide should be refrigerated between 36 and 46°F, stored away from light, and not used beyond the expiration date stamped on the carton.

• After first use, store pramlintide at room temperature or keep at a temperature not greater than 86°F and discard after 30 days.

• Pramlintide is a Category C drug and should not be used in pregnancy unless the physician (prescriber) recommends otherwise based on individual situations.

• If nausea occurs with pramlintide use, it tends to be mild to moderate and transient and dissipates over time.

• Patients should contact their diabetes care provider if nausea is persistent or severe.

• If a dose of pramlintide is missed, patients should omit the missed dose and resume the prescribed dose with the following meal. Patients should never double the dose of pramlintide.⁸ 

• If pramlintide therapy is discontinued for any reason (e.g., surgery or illness), the same initiation protocol should be followed when therapy is resumed.⁸ 

• A study conducted in patients with type 1 diabetes using insulin pump therapy along with pramlintide found that a minimal reduction in mealtime insulin was needed when using an extended bolus, under physician supervision, to deliver the insulin.³⁵ 

• To minimize nausea, patients can try avoiding both higher-fat foods and lying down after eating and paying attention to feelings of fullness as a cue to stop eating.

A comprehensive diabetes education program should also inform patients about self-management practices to enhance success with any medication therapy.³⁴  Those include, but are not limited to, SMBG, meal planning, physical activity, recognition and management of hypoglycemia and hyperglycemia, and assessment of diabetes-related complications. In addition, it is equally important to provide training specific to troubleshooting special situations, such as illness or stress, inadequate or omission of insulin dose, inadvertent administration of increased insulin or pramlintide doses, inadequate food intake, or missed meals.^8,34 

Because pramlintide has the potential to delay the absorption of concomitantly administered oral medications, when the rapid onset of a concomitant orally administered agent is a crucial determinant of effectiveness (such as analgesics), patients should be counseled to take the agent at least 1 hour before or 2 hours after their pramlintide injection. Because of pramlintide's effect on gastric emptying, patients taking drugs that alter gastrointestinal motility (e.g., anticholinergic agents such as atropine) and agents that slow the intestinal absorption of nutrients (e.g., alpha-glucosidase inhibitors) are not candidates for this drug.⁸ 

After patients have been properly educated about normal physiology and the missing hormones in diabetes that are important to optimal glycemic control and pramlintide has been appropriately titrated in conjunction with suitable adjustments to mealtime insulin therapy, appropriate patient outcomes might include:

• Diminished daily blood glucose fluctuations

• Improved postprandial glycemic control

• Additional reductions in A1C

• Potential decrease in caloric intake that may result in weight loss

• Reductions in doses of total, short-, and long-acting insulin⁸ 

• Greater treatment satisfaction for patients with type 1 or type 2 diabetes compared to their counterparts using mealtime insulin without adjunctive pramlintide therapy^36,37 

Amylin receptor agonism is emerging as part of an integrated neurohormonal therapeutic approach for managing diabetes in those patients who are prescribed prandial insulin therapy. Through the three mechanisms of decreasing food intake, slowing the rate of gastric emptying, and reducing postprandial glucagon release in a glucose-dependent manner, pramlintide helps reduce the rate of glucose entry into the bloodstream to better match the ability of insulin to dispose of blood glucose in the postprandial state.³⁸  In addition to improvement in A1C, the use of pramlintide typically yields positive effects on body weight, providing a more physiological approach for glycemic management in people with type 1 or type 2 diabetes who use mealtime insulin.