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FIGURE 4 Pramlintide-reduced postprandial glucose concentrations. Patients with type 2 diabetes (n = 19) were administered placebo or 120 ^g pramlintide and rapid-acting insulin lispro immediately prior to a meal. Pramlintide significantly reduced glucose concentrations in the postprandial period compared to placebo (P< 0.05). Source: From Ref. 33.

6 months of pramlintide treatment, patients with type 2 diabetes lost an average of —1.5 kg compared with an average gain of + 0.2 kg in placebo-treated patients (Fig. 5) (30,31). Weight reductions were sustained for up to 1 year. Stratification of patients based on baseline body mass index demonstrated that body weight reductions were greatest in those who were overweight or obese (35). Furthermore, weight reduction in pramlintide-treated patients occurred without prescribed modification of diet or exercise routines (30,31) and was independent of nausea, a common side effect of pramlintide treatment (30).

In these initial long-term, placebo-controlled clinical trials investigators and patients were encouraged to maintain stable insulin dosages when pramlintide was introduced in order to isolate the effects of pramlintide. Additionally, the dose of pramlintide was not slowly up-titrated to the maintenance dose, in contrast to what is recommended today (20). As a result, an increased rate of severe hypoglycemia during the initial 3 months of pramlintide therapy was observed when compared to placebo (30,31). It is important to note that although pramlintide itself does not cause hypoglycemia, the addition of pramlintide to an insulin-based regimen can increase the risk of insulin-induced severe hypoglycemia. Therefore, proper mealtime insulin dose adjustments upon initiation of pramlintide therapy are very important to reduce the risk of hypoglycemia.

A subsequent 29-week, placebo-controlled, non-inferiority study was conducted in patients with type 1 diabetes using intensive insulin therapy (multiple daily injections or insulin pump) in order to determine a method of pramlintide initiation that would mitigate the increased risk of severe hypoglycemia (36). During initiation of therapy, pramlintide was escalated from 15 to 60 ^g per meal in 15-^g increments over 4 weeks and mealtime insulin was reduced by 30% to 50% on pramlintide initiation. The insulin dose was subsequently adjusted to optimize glycemic control in both the pramlintide- and placebo-treated groups. As expected, since both study arms were targeting similar glycemic parameters, A1c decreased comparably in the pramlintide + insulin group and the placebo + insulin group (—0.4% and —0.5%, respectively), despite reductions in insulin doses in the pramlintide-treated group (mealtime insulin: 28%; total daily insulin: 12%). Pramlintide-treated patients also experienced significant reductions in postprandial glucose excursions and had significant weight loss (—1.3 kg vs. + 1.2 kg) compared to subjects in the placebo group. These changes were all observed in the context of an improved safety profile compared with the previous long-term clinical studies. Patients with type 2 diabetes were not examined in this study; however, the study supports the pramlintide dose escalation and initial mealtime insulin dose reduction recommended upon pramlintide initiation in patients with type 2 diabetes (20).

Open-Label Clinical Study

This method of pramlintide initiation was assessed in a 6-month open-label clinical practice study. Patients with type 2 diabetes were instructed to reduce mealtime insulin by 30% to 50% upon pramlintide (120 ^g) initiation. In this study, despite significant reductions in mealtime and total insulin doses of —10.3% and —6.4%, respectively (P < 0.05), significant A1c reductions

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