Sustained weight loss following 12-month pramlintide treatment as an adjunct to lifestyle intervention in obesity

OBJECTIVE—To assess long-term weight loss efficacy and safety of pramlintide used at different dosing regimens and in conjunction with lifestyle intervention (LSI).RESEARCH DESIGN AND METHODS—In a 4-month, double-blind, placebo-controlled, dose-ranging study, 411 obese subjects were randomized to receive pramlintide (six arms: 120, 240, and 360 μg b.i.d. and t.i.d.) or placebo in conjunction with a structured LSI program geared toward weight loss. Of the 4-month evaluable subjects (n = 270), 77% opted to continue preexisting treatment during an 8-month single-blind extension (LSI geared toward weight maintenance).RESULTS—At month 4, mean weight loss from baseline in the pramlintide arms ranged from 3.8 ± 0.7 to 6.1 ± 0.8 kg (2.8 ± 0.8 kg with placebo). By month 12, initial 4-month weight loss was regained in the placebo group but was maintained in all but the 120-μg b.i.d. group. Placebo-corrected weight loss with 120 μg t.i.d. and 360 μg b.i.d. averaged 3.2 ± 1.2 kg (3.1 ± 1.1% body wt) and 3.3 ± 1.1 kg (3.1 ± 1.0% body wt), respectively, at month 4 (both P < 0.01; 4-month evaluable n = 270) and 6.1 ± 2.1 kg (5.6 ± 2.1% body wt) and 7.2 ± 2.3 kg (6.8 ± 2.3% body wt), respectively, at month 12 (both P < 0.01; 12-month evaluable n = 146). At month 12, 40 and 43% of subjects treated with 120 μg t.i.d. and 360 μg b.i.d., respectively, achieved ≥10% weight loss (vs. 12% for placebo). Nausea, the most common adverse event with pramlintide in the 4-month study (9–29% pramlintide vs. 2% placebo), was generally mild to moderate and occurred in <10% of subjects during the extension.CONCLUSIONS—When used over 12 months as an adjunct to LSI, pramlintide treatment, with low-dose three-times-daily or higher-dose two-times-daily regimens, helped obese subjects achieve greater initial weight loss and enhanced long-term maintenance of weight loss.To date, efforts to develop obesity pharmacotherapies aimed at reducing food intake and body weight have largely focused on small-molecule anorectics, an approach that has repeatedly been hampered by safety concerns (1). Peptide hormones originating from pancreas and gut regulate meal size and body weight by acting as short-term (episodic) signals (2). In contrast to small molecules, peptide hormones do not readily diffuse the blood-brain barrier to penetrate the entire central nervous system. Moreover, they act by enhancing signaling through specific, naturally occurring pathways that regulate food intake as opposed to acting more generally on multiple neuronal processes, for example, by altering synaptic concentrations of neurotransmitters. Based on these characteristics, peptide hormone therapeutics are potential alternatives to centrally-acting small-molecule anorectics.Amylin, a 37–amino acid β-cell hormone cosecreted with insulin in response to meals, reduces food intake and body weight in rodents and may fulfill the criteria for a peripheral satiation hormone (3–6). Pramlintide, a synthetic analog of human amylin, has been extensively studied as an antihyperglycemic treatment and is currently under investigation as a potential treatment for obesity.In two studies in obese subjects, pramlintide (120 μg single doses or 180 μg t.i.d. before meals for 6-weeks) reduced ad libitum food intake (7,8). Compared with placebo, pramlintide significantly reduced 24-h caloric intake (by ～500–750 kcal) and caloric intake at a highly palatable fast-food challenge (by ～20%) and improved control of eating, evidenced by a 45% reduction in binge-eating score (8).Pramlintide''s weight effects in obese subjects were initially assessed in a 16-week, randomized, double-blind, placebo-controlled, nonforced dose-escalation study. In this study, in which 88% of subjects escalated to the maximum dose (240 μg t.i.d.), pramlintide induced a placebo-corrected reduction in weight of 3.7% (P < 0.001), with 31% of pramlintide-treated subjects achieving ≥5% weight loss (versus 2% for placebo; P < 0.001) (9). Although these findings established a solid proof of concept for the antiobesity potential of pramlintide, the study was limited to 4 months and did not employ lifestyle intervention (LSI), and subjects were not randomly assigned to different pramlintide doses or dose frequencies.To evaluate the weight loss efficacy and safety of pramlintide across a range of doses, across different dose frequencies, in conjunction with LSI, and over 1 year, we conducted a 4-month dose-ranging study (main study) evaluating six pramlintide arms (120, 240, and 360 μg b.i.d. and t.i.d.) in conjunction with lifestyle intervention (LSI) and then implemented an 8-month single-blind extension protocol in which subjects continued their preassigned treatment.