Studies in Type Diabetes

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When administered in physiologic doses to people with type 1 diabetes, injections of pramlintide result in sustained reductions in A1c associated with significant blunting of the glucose response to a standardized meal. In addition, significant reductions in the postprandial concentrations of triglycerides, and of several measures of oxidative stress:

nitrotyrosine, oxidated-LDL, and total radical-trapping antioxidant parameter have been reported (28-30).

Several long-term, randomized, placebo-controlled trials of pramlintide in people with type 1 diabetes have shown consistent reductions in A1c accompanied by modest weight loss. In all of the studies, patients treated with pramlintide experienced a two- to threefold higher rate of nausea than those in the placebo group. Most of the nausea was described as mild to moderate and tended to decrease in frequency and severity with time (31-33). In one study, only 7.4% of subjects on pramlintide discontinued the study due to nausea (33). In a large 52-week trial, the SC administration of 60 ^g of pramlintide three or four times per day led to a reduction in A1c of 0.29% and 0.34%, respectively. Both groups treated with pramlintide experienced a modest weight loss of 0.4 kg, compared to weight gain of 0.8 kg in the placebo group. Those treated with pramlintide experienced a fourfold higher rate of severe hypoglycemia, the frequency of which decreased to levels below that of the placebo group after the first 4 weeks. Investigators were asked to maintain constant insulin doses, unless hypoglycemia occurred (32). In contrast, the SC administration of 30 and 60 ^g of pramlintide in another trial resulted in a placebo-adjusted 0.27% reduction in A1c and 1.5 kg weight loss without an increase in risk of severe hypoglycemia. The lower rate of severe hypoglycemia in this study is likely due to the protocol allowance of investigator-initiated reductions in the dose of insulin at the initiation of study drug.

Analysis of the results of these trials prompted the manufacturer to recommend aggressive reduction in prandial insulin doses upon the introduction of pramlintide. A recent study, comparing the addition of pramlintide or placebo to maximized insulin therapy, showed that a prospective 30% to 50% reduction in prandial insulin dose resulted in a marked reduction in the risk of severe hypoglycemia in both groups. Starting at a baseline average 8%, A1c was reduced by 0.5% in both groups, but those on pramlintide experienced weight loss, lower postprandial glucose levels and lower triglyceride levels (31). Subjects treated with continuous SC insulin infusion were evaluated with continuous glucose monitoring before, during, and after 30 ^g pramlintide t.i.d. was added to their preexisting regimen. To avoid hypoglycemia, the baseline insulin dosage was reduced by at least 10% at the initiation of pramlintide therapy. Compared to baseline measures, mean 24-hour glucose concentration was significantly reduced by the addition of 30 ^g pramlintide t.i.d. to preexisting continuous SC insulin infusion. The number of glucose measurements above 140 mg/dL decreased from 59% to 48%, without an increase in those below 80 mg/dL (29).

The optimal timing of pramlintide was studied in 38 subjects with type 1 diabetes given a standardized mixed meal. Insulin doses were adjusted before the study, but kept constant for each of the five meal tests. Relative to the meal, the subjects were given regular insulin at -30 minutes or insulin lispro at 0 minute in addition to either placebo at -15 minutes or pramlintide 60 ^g at -15, 0, +15, and +30 minutes. Glucose area under the curve was significantly lower after each pramlintide treatment, but only preprandial pramlintide dosing blunted the immediate postprandial rise. Those receiving insulin lispro and pramlintide immediately before meals had a reduction in glucose at 60 minutes but experienced a gradual rise in glucose for the remainder of the 6-hour study. Postprandial glucose levels appeared to be more stable in those treated with regular insulin. There were no episodes of severe hypoglycemia in this study (34) (Fig. 2).

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