Anne Peters, MD, and Lori Laffel, MD, MPH, editors
Jane Lee Chiang, MD, managing editor
Jeremy Hodson Pettus, MD, and Steven Edelman, MD
Weight gain is associated with intensive insulin regimens. During the first year of the DCCT, subjects assigned to intensive insulin therapy gained twice as much weight as those given conventional therapy.12 This increased weight is concerning in diabetes as it can lead to and exacerbate factors such as hypertension and hyperlipidemia that place patients at even higher risk for cardiovascular complications. Fortunately, improved glycemic control in pramlintide-treated patients in long-term, placebo-controlled studies was not accompanied by weight gain, but instead was associated with a sustained and significant reduction in body weight. Following 6 months of pramlintide treatment, patients with T1D lost an average of approximately 1 kg compared with an average gain of 0.6 kg in placebo-treated patients (see Figure 13.5).28,31 Weight reductions were sustained up to 1 year, however, in an open-label extension trial, patients who continued on pramlintide tended to begin to regain weight. Stratification of patients based on baseline body mass index demonstrated that body weight reductions were greatest in patients who were over-weight or obese, and that pramlintide did not change weight in lean patients….
Hypoglycemia was a concern highlighted by the early pivotal trials. This side effect was typically noticed in the initiation of the medication (first 4 weeks) without any proactive reduction in insulin dosing and no titration of the dose, both of which led to an FDA black box warning. To address initiation strategies, a 29-week, placebo-controlled dose titration study was conducted in which pramlintide was initiated at 15 mcg with a 30–50% proactive reduction in meal-time insulin dosing.
Figure 13.5 Effects from combined placebo-controlled trials on A1C, insulin dose, and weight. Source: Taken from: Edelman SV, Darsow T, Frias JP: Pramlintide in the treatment of diabetes. Int J Clin Pract 60:1647–1653, 2006. Reprinted with permission from the publisher.
Pramlintide was then increased to a goal dose of 60 mcg before meals as tolerated with insulin doses adjusted to blood glucose values. Using this strategy, hypoglycemic events during initiation of pramlintide were reduced and not statistically different from placebo. Consistent with previous studies, significant reductions in postprandial glucose, insulin dose, and weight were observed.33
Hypoglycemia. Pramlintide does not cause hypoglycemia when administered alone. However, the addition of an antihyperglycemic agent to a patient’s insulin therapy has the potential to increase the risk of insulin-induced hypoglycemia, particularly at the start of therapy. As mentioned above, hypoglycemia was observed more frequently in the initial trials when insulin doses were not prophylactively reduced and pramlintide was initiated at the highest recommended dose of 60 mcg. It has since been demonstrated that this risk was short-term and manageable with adequate glucose monitoring, a 30–50% reduction of preprandial insulin doses at initiation of pramlintide, and gradual upward titration of the pramlintide dose during its initiation.33
Gastrointestinal. Beyond hypoglycemia, the most common side effects seen with pramlintide are nausea followed by anorexia and vomiting.28,31 Nausea is particularly an issue in the T1D population, with rates as high as 48% in the initiation period. Practitioners and patients need to be aware of this common phenomenon and address it specifically at the time of initiation. It seems as though, based on the authors extensive clinical experience, the longer the duration of T1D, the more susceptible the individual is to nausea. With diligent slow up-titration, the effect can be minimized. Furthermore, it should be emphasized to the patient that the gastrointestinal side effects are typically mild to moderate in intensity and transient. However, given that pramlintide slows the rate of gastric emptying, this can lead to more severe symptoms in patients with established gastroparesis.
Pramlintide is an appropriate adjunct to mealtime insulin to consider for any patient with T1D that is not meeting their desired A1C goal. However, there are some basic concepts to keep in mind prior to initiation. Patients should begin with reasonable blood glucose control with an A1C <9% indicating a somewhat stable insulin regimen and compliance with their insulin therapy. Patients should monitor their blood glucose frequently (or use a continuous glucose monitor) and have frequent contact with a health care provider skilled in insulin use. Pramlintide should be avoided in patients with hypoglycemia unawareness or with episodes of severe hypoglycemia in the preceding 6 months. Patients with severe gastroparesis should not use pramlintide as its effect on slowing gastric emptying can exacerbate these symptoms. In patients with mild gastroparesis the effects of pramlintide can actually improve symptoms because it helps to prevent over eating, which makes the stomach wall atonic. The pramlintide dose should be gradually titrated upwards with an initial 50% decrease in mealtime insulin. In the clinical trials the final reduction in mealtime insulin was ~30% so a discussion should be held with the patient telling them that the 50% may be too much and to expect higher blood glucose values upon initiation. Doses of both pramlintide and insulin should be adjusted according to the patient based on symptoms and home or continuous glucose monitoring. Figure 13.6 details dose titration when initiating pramlintide.
The timing of the mealtime insulin bolus should also be taken into consideration. Pramlintide reduces the postprandial glucose concentrations via the mechanisms described above. Dosing a rapid-acting insulin analog before a meal in a typical fashion may result in an initial reduction in postprandial glucose, but can also result in a late, gradual increase in glucose concentrations after peak mealtime insulin action (see Figure 13.3). Experimenting with dosing the rapid- acting analog insulin after the meal or using an extended wave bolus via an insulin pump may help to further fine-tune the overall postprandial glucose profile in patients using pramlintide and provide a better matching of the pharmacokinetics of rapid-acting insulin.
Pramlintide is currently FDA-approved for adults but not in the pediatric population; however, several small trials have evaluated its use in children and
Figure 13.6 Stepwise approach to initiating pramlintide therapy. Adapted from: Pramlintide Acetate Prescribing Information [package insert], 2005
adolescents.34–37 Overall, these trials have demonstrated similar effects as seen in the adult population in regard to decreasing postprandial hyperglycemia, reducing insulin dose, and improving body weight profiles — an overall proof of concept. The aim of these trials has largely been to establish a safe dose that can be administered without undue side effects. Pramlintide is frequently used in the adolescent population; however, this is an off-label indication. A 4-month trial comparing pramlintide with insulin vs. exenatide and insulin in 12–21 year olds is currently underway and may help answer some of these questions.
Future Roles of Pramlintide in Insulin Pumps and the Artificial Pancreas
With the improvement in continuous glucose monitors, insulin pumps, and insulin formulations, the artificial pancreas has become an increasingly possible technology. Studies have commenced testing prototype models for at home use in real-world situations.38 However, the lag time between insulin infusion in the subcutaneous tissue and its onset of metabolic action remains a significant barrier to perfecting the insulin delivery algorithms. This lag can result in unacceptable postprandial glucose spikes with potential late hypoglycemic reactions. To solve this problem, one could imagine multiple possible solutions. One solution would be to add pramlintide into the infusion device itself along with insulin to help mitigate postprandial hyperglycemia. This addition, however, would mean a separate chamber for pramlintide in the device with a separate infusion site since the two medications are currently believed to be incompatible. Furthermore, the larger clinical trials above only assessed pramlintide as an adjunct in a mealtime fashion. Therefore, it remains to be seen if infusion of the medication in a basal-bolus fashion would confer any additional benefits beyond mealtime delivery alone.
Several small trials have begun to address these issues. A 16-week open-label study of 11 patients with long-standing T1D used pramlintide in a basal-bolus fashion administered via an insulin pump. A continuous infusion was maintained at 9 mcg/hr with boluses at mealtime titrated up to 60 mcg. Over the study period, patients had lower A1C values, and lower fasting glucoses, and lost weight.39 However, there was no control group that used pramlintide in a bolus fashion only, making it impossible to determine the benefit of a continuous infusion. A similar study was done in adolescents where 13 patients were observed on insulin monotherapy and then crossed over to insulin along with pramlintide in a basal-bolus fashion.40 Improvement in glucose variability, reduction in insulin dose, and decreased glucagon response were all observed with the addition of pramlintide. Together these trials show that it is technically possible and safe to administer pramlintide in a continuous fashion along with insulin therapy. However, larger studies need to be done with an appropriate control group.
The need for separate infusions of pramlintide and insulin is cumbersome. To address this issue, one randomized, placebo-controlled study of 51 patients evaluated the effects of mixing various insulin formulations with pramlintide and ultimately found that this had no effect on the area under the concentration-vs.-time curve and the maximum concentration of serum-free insulin.41 However, it remains unknown if the two can be mixed in a pump.
Pramlintide has been shown to be a useful addition to insulin in the treatment of T1D. Not only has it been shown to reduce A1C in the adult population but it does so while reducing overall insulin dose and weight. Furthermore, with proper dose titration at initiation, side effects can be effectively reduced, making the medication safe and tolerable. Going forward, the medication will need to be evaluated in the pediatric population, and if deemed safe and effective, would add a long-awaited adjunct in this group. Finally, with the advent of the artificial pancreas looming in the near future, the role of pramlintide in a continuous infusion setting along with insulin needs to be evaluated. The beneficial postprandial glucose profile provided by pramlintide could potentially help to close the loop sooner.
Next text: Part 3 – Adjunctive Therapies
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Used with permission by the American Diabetes Association. Copyright © 2013 American Diabetes Association.
Please note: We are proud to have Dr. Anne Peters as a member of our Advisory Board member for Diabetes In Control, Inc.