Steve V. Edelman, MD
Robert R. Henry, MD
Clinical Practice Study
In order to assess the efficacy and safety of pramlintide in a typical clinical practice setting, an open-label study was performed in 166 insulin-using patients with Type 2 diabetes who were not able to achieve glycemic control using insulin alone.
In this study, pramlintide was initiated at a dose of 120 mcg at major meals. Patients were instructed to reduce their mealtime insulin dose by 30% to 50% upon initiation of pramlintide, then they subsequently adjusted their insulin regimen according to premeal and postmeal glucose monitoring once pramlintide therapy was established. At 6 months, there was a baseline-subtracted A1c reduction of -0.56% from baseline and a body weight reduction of -2.76 kg from baseline. Pramlintide significantly reduced both fasting and PPG (Figure 11.5). These changes were achieved with dose reductions of total, short-acting, and long-acting insulin (-6.4%, -10.3%, and -4.20%, respectively).
FIGURE 11.4 — Change in A1C and Body Weight Over 52 Weeks in 656 Patients with Type 2 Diabetes Treated with Insulin Plus Various Doses of Pramlintide
Change from baseline in mean A1C (A) and body weight (kg) (B). * P = 0.01 compared with placebo. Adapted from Hollander PA, et al. Diabetes Care. 2003;26:784-790.
Weight-Loss Effects of Pramlintide
As noted, several long-term, placebo-controlled clinical studies have shown that improved glycemic control in pramlintide-treated patients was not accompanied by increased body weight. The greater reduction in A1c with pramlintide compared with placebo has been associated with a sustained and statistically significant reduction in body weight. These findings are further supported by the results of a pooled post hoc analysis of data from 498 overweight/obese (BMI 40 kg/m2 and in those treated with MET.
After 6 months of pramlintide therapy as an adjunct to mealtime insulin, postprandial glucose excursions and glucose fluctuations throughout the day were reduced in patients with Type 2 diabetes. *P
Pramlintide treatment has been generally well tolerated in patients with diabetes. No evidence of cardiac, hepatic, or renal toxicity, changes in serum lipids, or clinically relevant changes in laboratory parameters, vital signs, electrocardiograms, or abnormal findings upon physical examinations have been observed.
In patients with Type 2 diabetes, the most common adverse events, other than hypoglycemia, were GI, including nausea (30%) and vomiting (7%). These symptoms, particularly nausea, appeared early after initiation of therapy, were mostly of mild-to-moderate intensity, were dose dependent, and resolved over time. Slow titration of pramlintide has been shown to significantly reduce the incidence of nausea.
While hypoglycemia is more of a concern in patients with Type 1 diabetes, pramlintide, which is used with insulin, has been associated with an increased risk of insulin-induced severe hypoglycemia in both Type 1 and Type 2 diabetes. When severe hypoglycemia associated with pramlintide occurs, it is usually seen within the first 3 hours after pramlintide injection. Pramlintide alone (without concomitant insulin use) does not cause hypoglycemia.
It should be emphasized that the addition of any antihyperglycemic agent to a patient’s current insulin therapy has the potential to increase the risk of insulin-induced hypoglycemia, particularly at the start of therapy. In one of the initial long-term pivotal studies of patients with Type 1 and insulin-requiring Type 2 diabetes where full dose pramlintide was added to existing insulin regimens in double-blind fashion without titration, it was observed that the severe hypoglycemia event rate during the first 4 weeks of therapy was higher in the pramlintide group compared with the placebo group. In another study in patients with Type 1 diabetes, it was shown that this risk was short-term and manageable with adequate glucose monitoring, a 30% to 50% reduction of premeal insulin doses at initiation of pramlintide, and gradual upward titration of the pramlintide dose during its initiation. In the previously discussed clinical practice study, in patients with Type 2 diabetes, proactive reduction in premeal insulin doses at initiation of pramlintide was also shown to reduce the incidence of hypoglycemia.
Dosing of Pramlintide
Pramlintide is available in a 60 mcg or 120 mcg pen. Patients with Type 2 diabetes generally use the 120mcg pen which delivers doses of either 60 or 120 mcg. Pramlintide should always be administered at a distinct injection site >2 inches away from concomitant insulin injections. All patients should reduce premeal insulin by 50% to lessen the risk of insulin-induced hypoglycemia, monitor blood glucose frequently, and contact their health care provider if symptoms of nausea and/or hypoglycemia are severe or unusually persistent and when the dosage of pramlintide or insulin is changed. General guidelines and dosing for patients with Type 2 diabetes:
• Initiate pramlintide at the 60 mcg dose taken immediately prior to major meals
• Titrate pramlintide to 120 mcg dose after 3 or more days with no clinically significant nausea
• Optimize insulin to achieve glycemic targets once the maintenance dose of pramlintide is reached and blood glucose concentrations are stable.
Practical Tips for Patients on Pramlintide
- Start With a Low Dose and Titrate Slowly — Pramlintide can cause nausea, anorexia, and vomiting, especially in Type 1 diabetes where a more gradual titration is required. It is extremely important not to rush the dose titration. Patients with Type 2 diabetes generally experience fewer GI side effects. In patients with Type 2 diabetes, start with a dose of 60 mcg, followed by escalation to the final dose of 120 mcg if the patient is asymptomatic. If the patient experiences nausea or other GI side effects, do not increase the dose of pramlintide until the GI side effects dissipate.
- Take Pramlintide Just Prior to the Meal — In a dose-timing study of pramlintide, PPG concentrations were lowered most effectively when pramlintide was administered just before the meal (Figure 11.3). This reduction of PPG occurred whether the patient was using insulin lispro or regular insulin.
- When Initiating Pramlintide, Decrease Dose of Mealtime Insulin by 50% — Pramlintide not only works to reduce glucose appearance via the mechanisms previously described but it may also lead to a reduction in food intake greater than anticipated by a patient newly starting pramlintide. Further adjustments of the insulin dose either up or down should be based on home glucose monitoring results and experience with pramlintide.
- Timing of the Insulin Dose May Be Important — Many patients who have experience with pramlintide take a fast-acting insulin analog as they approach the end of a meal. The reason is because they will know how much and what types of food they have eaten, so the insulin-dose calculation using carbohydrate counting or other means will be more accurate. Pramlintide delays gastric emptying, and thus the peak in PPG may overlap with the peak action of the fast-acting analogs when given a little later than the beginning of the meal.
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