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Component Description FDA = Food and Drug Administration; HbA1c=glycated hemoglobin. Population Adults and children with type 1 or type 2 diabetes Intervention Pramlintide for FDA- and non-FDA-approved indications Compared agent Other hypoglycemic agent or placebo Long-term health outcomes All-cause mortality, micro- or macrovascular disease, quality of life, complications related to diabetes Intermediate outcomes Glycemic control: HbA1c, fasting plasma glucose, postprandial glucose; change in weight; time to treatment failure Harms-related outcomes Withdrawals due to all causes, withdrawals due to adverse events, overall adverse events, major adverse events Study design For efficacy/effectiveness: randomized controlled clinical trials, good-quality systematic reviews For harms and subgroups: randomized controlled clinical trials, good-quality systematic reviews, population-based comparative cohort or case-control studies Excluded Trials <12 weeks’ duration; abstracts, posters, and conference proceedings with limited information for quality assessment Study Sample at Baseline (Mean) Author, Year, Quality N Duration, wk Age, y Male, % White, % Duration of Diabetes, y HbA1C, % Weight, kg Total Daily Insulin Dose Units Pramlintide Dose and Titration Schedule bid = 2 times daily; CSII = continuous subcutaneous insulin infusion; HbA1c = glycated hemoglobin; MDI = multiple daily injections; NR = not reported; qid = 4 times daily; tid = 3 times daily. Type 1 diabetes Whitehouse et al, 2002,10 Fair-poor 480 52 40.3 55.0 94.0 16.8 8.8 75.3 NR 30 μg tid-qid before meals + flexible-dose insulin. If HbA1c level decreased by <1%, patients were re-randomized to 30 μg or 60 μg. If change in HbA1C level was ≥1%, patients continued with 30 μg Edelman et al, 2006,5 Fair 296 29 41.0 45.1 88.7 20.0 8.2 80.0 MDI: 65.1 CSII: 47.8 15 μg and titrated to 60 μg tid-qid before meals + flexible-dose insulin. Patients unable to tolerate maintenance dose had dose lowered to 30 μg or 15 μg. A 30%-50% reduction in prandial insulin was allowed Ratner et al, 2004,7 Fair-poor 651 52 40.5 50.0 90.5 18.7 9.0 77.1 NR 60 μg tid-qid or 90 μg tid before meals + fixed-dose insulin. If nausea occurred within 2 wk of study, dose could be lowered by up to 50% for up to 2 wk Type 2 diabetes Riddle et al, 20079 Fair 212 16 55.0 48.8 72.5 12.2 8.5 103.0 51.0 60 μg and titrated to 120 μg bid-tid before meals + flexible-dose glargine ± metformin, sulfonylurea, and/or thiazolidinedione Ratner et al, 20028 Fair-poor 538 52 56.5 59.0 78.5 12.3 9.2 NR 57.9 30 μg, 75 μg, or 150 μg tid before meals + fixed-dose insulin and/or metformin, sulfonylurea Hollander et al, 20036 Fair 656 52 56.7 50.0 75.0 12.2 9.2 96.9 NR 60 μg tid, 90 μg bid, or 120 μg bid before meals + fixed-dose insulin and/or metformin, sulfonylurea. 60-μg dose study arm was excluded from efficacy analyses Trial, Duration Change in HbA1cLevel % (95% CI) PValue Change in PPG, mg/dL PValue Change in Weight, kg PValue HbA1c=glycated hemoglobin; CI=confidence interval; NR = not reported; PPG = postprandial glucose; qid = 4 times daily; tid = 3 times daily. aChange from baseline to 3 hours postprandial. bCompared with placebo. Edelman et al, 2006,5 29 wk Pramlintide, 30 or 60 μg tidqid 0.50 (−0.61 to −0.33) – −34a NR −1.3 <.001b Placebo −0.50 (−0.63 to −0.35) – −18a NR 1.2 Whitehouse et al, 2002,10 52 wk Pramlintide, 30 or 60 μg qid −0.39 .007b NR – −0.5 NR Placebo −0.12 NR – +1.0 NR Ratner et al, 2004,7 52 wk Pramlintide, 60 μg tid −0.29 .011b NR – −0.4 .027b Pramlintide, 60 μg qid −0.34 .001b NR – −0.4 .04b Placebo −0.04 NR – +0.8 Trial, Duration Change in HbA1c Level, % PValue Change in PPG, mg/dL PValue Change in Weight, kg PValue HbA1c = glycated hemoglobin; bid = 2 times daily; NR = not reported; PPG = postprandial glucose; tid = 3 times daily. aCompared with placebo. bCompared with placebo for both dosages combined. Riddle et al, 2007,9 16 wk Pramlintide, 60 or 120 μg bid-tid −0.70 <.05a −24.4 <.001a −1.6 <.001a Placebo −0.36 −0.4 +0.7 Ratner et al, 2002,8 52 wk Pramlintide, 75 μg tid −0.50 >.05a NR −0.5 <.001a Pramlintide, 150 μg tid −0.60 <.001a NR −1.4 <.001a Placebo −0.20 NR +1.0 Hollander et al, 2003,6 52 wk Pramlintide, 90 μg bid −0.35 NR −0.5 Pramlintide, 120 μg bid −0.62 <.001b NR −1.25 <.003b Placebo −0.22 NR +0.6 - Table 5.
Frequency of Adverse Events in Placebo-Controlled Studies of Pramlintide in Type 1 Diabetes
Trial Any Nausea % Severe Nausea % Any Anorexiaaor Reduced Appetite % Severe Anorexia or Reduced Appetite % Any Vomiting % Severe Vomiting % aAnorexia was defined as decreased appetite, early satiety or gastric fullness, loss of appetite, or no appetite. bThe rate of 95.1% occurred in persons in the pramlintide 30-μg group. Edelman et al, 20065 Pramlintide 48.5–95.1b 4.0–7.3 6.9–14.6 0.0 11.9–17.1 2.4–5.9 Placebo 36.1 0.7 2.0 0.0 6.1 0.7 Whitehouse et al, 200210 Pramlintide 46.5 6.2 17.7 2.5 11.5 2.1 Placebo 21.9 1.7 2.1 0.0 8.0 0.4 Ratner et al, 20047 Pramlintide 47.9–59.0 5.8–8.5 11.0–18.0 0.6–1.9 9.8–12.0 0.6–1.8 Placebo 12.0 1.3 2.6 0.0 6.5 0.6 - Table 6.
Severe Hypoglycemic Events in Placebo-Controlled Trials of Pramlintide in Type 1 Diabetes
Events per Patient-YearaMean No. (SE) Trial Weeks 0–4 Weeks 0–29 Weeks 26–52 qid = 4 times daily; SE = standard error; tid = 3 times daily. aEvent rates were calculated as the total number of events for all patients on a treatment regimen divided by the total number of patient-years of observation. bEvent rates were calculated after excluding 1 patient in the placebo group who reported >100 episodes of severe hypoglycemia. Edelman et al, 20065 Pramlintide, 30 μg tid-qid 0.79 (0.46) 1.10 (0.25) – Pramlintide, 60 μg tid- qid 0.46 (0.46) 0.42 (0.09) – Placebo 0.42 (0.19) 0.30 (0.06) – Whitehouse et al, 200210 Pramlintide, 30 or 60 μg tid-qid 2.12 (0.35) – 0.43 (0.07) Placebo 1.04 (0.24)b – 0.52 (0.08)b Ratner et al, 20047 Pramlintide, 60 μg tid 3.78 (0.57) – 0.74 (0.12) Pramlintide, 60 μg qid 3.41 (0.55) – 0.79 (0.12) Pramlintide, 90 μg tid 3.91 (0.58) – 0.64 (0.12) Placebo 0.87 (0.27) – 0.45 (0.09)
Additional Files
The Article in Brief
Efficacy and Harms of the Hypoglycemic Agent Pramlintide in Diabetes Mellitus
Susan L. Norris , and colleagues
Background This study examined existing evidence about the efficacy, effectiveness, and harms of pramlintide, a new drug that complements insulin for maintaining glycemic and weight control in adults and children with type 1 or type 2 diabetes.
What This Study Found The study found that pramlintide was modestly effective. It improved glycated hemoglobin levels by 0.2 to 0.4 percent compared with placebo in both type 1 and type 2 diabetes populations, except when type 1 was managed with intensive insulin treatment, for which there was no significant difference between groups. Weight loss was observed with pramlintide in both type 1 and type 2 diabetes, whereas placebo-treated patients tended to gain weight. There was little evidence to suggest that pramlintide is significantly better than placebo at reducing fasting plasma glucose levels, postprandial glucose levels, or total insulin dose. Moreover, pramlintide-treated patients experienced more frequent nausea and severe hypoglycemia compared with patients treated with placebo.
Implications
- The authors conclude that although improvements in glycated hemoglobin levels were small, incremental improvements from the addition of pramlintide may ultimately contribute to long-term glycemic control and cardiovascular health when combined with other means of improving glycemic control.
- Further studies are needed to evaluate the long-term health outcomes and adverse events associated with pramlintide to determine whether the benefits outweigh risks.
