Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy.
The neurohormonal control of body weight involves a complex interplay between long-term adiposity signals (e.g., leptin), and short-term satiation signals (e.g., amylin). In diet-induced obese (DIO) rodents, amylin/leptin combination treatment led to marked, synergistic, fat-specific weight loss. To evaluate the weight-lowering effect of combined amylin/leptin agonism (with pramlintide/metreleptin) in human obesity, a 24-week, randomized, double-blind, active-drug-controlled, proof-of-concept study was conducted in obese or overweight subjects (N = 177; 63% female; 39 +/- 8 years; BMI 32.0 +/- 2.1 kg/m(2); 93.3 +/- 13.2 kg; mean +/- s.d.). After a 4-week lead-in period with pramlintide (180 microg b.i.d. for 2 weeks, 360 microg b.i.d. thereafter) and diet (40% calorie deficit), subjects achieving 2-8% weight loss were randomized 1:2:2 to 20 weeks of treatment with metreleptin (5 mg b.i.d.), pramlintide (360 microg b.i.d.), or pramlintide/metreleptin (360 microg/5 mg b.i.d.). Combination treatment with pramlintide/metreleptin led to significantly greater weight loss from enrollment to week 20 (-12.7 +/- 0.9%; least squares mean +/- s.e.) than treatment with pramlintide (-8.4 +/- 0.9%; P < 0.001) or metreleptin (-8.2 +/- 1.3%; P < 0.01) alone (evaluable, N = 93). The greater reduction in body weight was significant as early as week 4, and weight loss continued throughout the study, without evidence of a plateau. The most common adverse events with pramlintide/metreleptin were injection site events and nausea, which were mostly mild to moderate and decreased over time. These results support further development of pramlintide/metreleptin as a novel, integrated neurohormonal approach to obesity pharmacotherapy.
Ravussin
Eric
E
Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA.
Smith
Steven R
SR
Mitchell
Julie A
JA
Shringarpure
Reshma
R
Shan
Kevin
K
Maier
Holly
H
Koda
Joy E
JE
Weyer
Christian
C
D050154:Adiposity / Q000187:drug effects; D000328:Adult; D000682:Amyloid / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019440:Anti-Obesity Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015992:Body Mass Index; D003131:Combined Modality Therapy; D004311:Double-Blind Method; D004338:Drug Combinations; D002149:Energy Intake; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D006801:Humans; D058228:Islet Amyloid Polypeptide; D020738:Leptin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000188:drug therapy*; D050177:Overweight / Q000178:diet therapy / Q000188:drug therapy* / Q000378:metabolism; D058287:Receptors, Islet Amyloid Polypeptide; D054411:Receptors, Leptin / Q000819:agonists / Q000378:metabolism; D018000:Receptors, Peptide / Q000819:agonists / Q000378:metabolism; D012527:Satiation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D015431:Weight Loss / Q000187:drug effects*
D000682:Amyloid; D019440:Anti-Obesity Agents; D004338:Drug Combinations; D058228:Islet Amyloid Polypeptide; C515448:LEPR protein, human; D020738:Leptin; D058287:Receptors, Islet Amyloid Polypeptide; D054411:Receptors, Leptin; D018000:Receptors, Peptide; C105254:pramlintide; C415771:metreleptin