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A recent commentary by Dr Louis Monnier1 in the April 2007 issue of Nature Clinical Practice Endocrinology & Metabolism questioned the benefit of pramlintide as an adjunct to mealtime insulin in patients with type 1 diabetes. We agree with Dr Monnier that any successful treatment for diabetes should be efficacious, safe, and consider the impact on the patient's quality of life. However, we differ with his assertion, based on results of a recently published clinical study, that pramlintide falls short on each of these parameters.
The results in question were from a placebo-controlled clinical study in patients with type 1 diabetes with a primary goal of assessing the safety and tolerability of pramlintide used as an adjunct to intensified insulin therapy. Pramlintide was initiated by dose-escalation to help mitigate nausea, and insulin was proactively reduced by 30–50% to reduce the risk of insulin-induced hypoglycemia, a significant departure from earlier studies where pramlintide was initiated at a fixed dose and insulin was not proactively reduced. While the primary endpoint was safety, the study was powered to assess non-inferiority of pramlintide in HbA1C compared with intensified insulin alone. Both pramlintide-treated patients and patients treated with insulin alone were targeting the same fasting and postprandial glucose goals, and as would be expected, similar reductions in HbA1C were observed. However, despite the fact that the glycemic goals of both treatment arms were the same, in pramlintide-treated patients the reduction in HbA1C was accompanied by several significant clinical benefits. First, pramlintide-treated patients experienced a significant and clinically meaningful reduction in body weight (−1.3 kg), as opposed to the weight gain observed in the patients treated with insulin alone (+1.2 kg) over the 29-week study. Weight gain of any kind is often a barrier to intensification of diabetes therapy in patients with either type 1 or type 2 diabetes, and these results demonstrate that improvements in glycemia can be achieved with weight loss. Second, pramlintide treatment also significantly improved postprandial glucose excursions while insulin treatment alone did not. These findings are consistent with previous studies demonstrating pramlintide's effect on lowering postprandial glucose excursions and variability.2,3 As was noted in the paper, it is likely that the late postprandial rise in blood glucose observed in the pramlintide-treated subjects explains the similar reduction in HbA1C, despite early improvement in postprandial glycemia, when compared with insulin alone. Appropriate insulin dosing strategies (e.g. end-of-meal insulin dosing, insulin pump extended bolus delivery), when pramlintide is used as adjunctive therapy, would provide better interprandial “coverage” and may improve overall mean blood glucose, leading to a further reduction in HbA1C. However, these insulin strategies were not feasible in a blinded study design.
Previous long-term clinical studies with pramlintide indicated an increased risk of insulin-induced hypoglycemia, particularly during initiation of pramlintide therapy. Contrary to Dr Monnier's suggestion, it is unlikely that pramlintide itself induces hypoglycemia risk by compromising glucagon response. In both healthy individuals and patients with diabetes, pramlintide does not interfere with the counter-regulatory hormone (including glucagon) and symptom response to experimental hypoglycemia.4,5,6,7 Severe hypoglycemia in previous pramlintide clinical studies was largely associated with lack of adjustment of mealtime insulin dose and initiation of pramlintide at full therapeutic dose. In the current study, pramlintide was titrated at initiation, thereby mitigating the impact of nausea, and with a proactive reduction in mealtime insulin dose, which resulted in lower rates of severe hypoglycemia than previously observed. While pramlintide-treated patients did experience more overall severe hypoglycemia than placebo-treated patients, it is important to note that the increase was in the minority of patients who experienced more nausea. The remaining cohort had hypoglycemic event rates indistinguishable from patients using insulin alone. Furthermore, when similar dosing strategies were used in a recent open-label clinical practice study using pramlintide, severe insulin-induced hypoglycemia was further reduced to event rates similar to those observed in reference populations of patients intensifying insulin therapy alone.8,9,10
The most common adverse event associated with pramlintide was mild-to-moderate nausea. While the pramlintide-treated patients had a higher incidence of nausea compared to placebo-treated patients, the dose escalation of pramlintide during initiation improved tolerability as reflected in the reduced withdrawal rate due to nausea (1.4% in current study compared to 9% in earlier clinical studies where pramlintide was not titrated).
Despite the fact that a greater percentage of patients treated with pramlintide in this study experienced adverse events and the speculation by Dr Monnier that this would negatively impact patient satisfaction, in a study-specific questionnaire administered under blinded conditions the pramlintide-treated patients instead reported significantly increased treatment satisfaction compared to insulin alone.11 Increased treatment satisfaction encompassed a number of parameters relating to diabetes treatment and quality of life. Pramlintide-treated patients reported increased satisfaction with weight and appetite control, consistent with the reduction in body weight that was observed, and a greater sense of overall health and well-being. In addition, significantly more patients felt that pramlintide provided more benefits than insulin alone.
Thus, contrary to Dr Monnier's opinion that “there are no evidence-based data to justify the clinical use of pramlintide,” there is a large body of evidence suggesting that replacement of amylin with pramlintide in patients with type 1 diabetes provides significant clinical benefits. These include improved glycemic control, weight management, and the ability to more effectively manage diabetes, effects not achievable with insulin use alone.
References
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SV Edelman has received research funding and honoraria, serves on the Advisory Board, and owns personal stock in Amylin Pharmaceuticals. S Garg has received research funding and honoraria, and is a member of the Speaker's Bureau of Amylin Pharmaceuticals. OG Kolterman is employed by, and owns stocks in, Amylin Pharmaceuticals.
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Edelman, S., Garg, S. & Kolterman, O. Is pramlintide a safe and effective adjunct therapy for patients with type 1 diabetes?. Nat Rev Endocrinol 3, E1 (2007). https://doi.org/10.1038/ncpendmet0506
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DOI: https://doi.org/10.1038/ncpendmet0506