Preclinical evidence suggests that
pharmacotherapy for
obesity using combinations of agents targeted at distinct regulatory pathways may produce robust additive or synergistic effects on
weight loss. This randomized placebo-controlled trial examined the safety and efficacy of the
amylin analogue
pramlintide alone or in combination with either
phentermine or
sibutramine. All patients also received lifestyle intervention. Following a 1-week placebo lead-in, 244 obese or
overweight, nondiabetic subjects (88% female; 41 +/- 11 years; BMI 37.7 +/- 5.4 kg/m(2); weight 103 +/- 19 kg; mean +/- s.d.) received placebo subcutaneously (sc) t.i.d.,
pramlintide sc (120 microg t.i.d.),
pramlintide sc (120 microg t.i.d.) + oral
sibutramine (10 mg q.a.m.), or
pramlintide sc (120 microg t.i.d.) + oral
phentermine (37.5 mg q.a.m.) for 24 weeks. Treatment was single-blind for subjects receiving subcutaneous medication only and open-label for subjects in the combination arms.
Weight loss achieved at week 24 with either combination treatment was greater than with
pramlintide alone or placebo (P < 0.001; 11.1 +/- 1.1% with
pramlintide +
sibutramine, 11.3 +/- 0.9% with
pramlintide +
phentermine, -3.7 +/- 0.7% with
pramlintide; -2.2 +/- 0.7% with placebo; mean +/- s.e.). Elevations from baseline in heart rate and diastolic blood pressure were demonstrated with both
pramlintide +
sibutramine (3.1 +/- 1.2 beats/min, P < 0.05; 2.7 +/- 0.9 mm Hg, P < 0.01) and
pramlintide +
phentermine (4.5 +/- 1.3 beats/min, P < 0.01; 3.5 +/- 1.2 mm Hg, P < 0.001) using 24-h ambulatory monitoring. However, the majority of subjects receiving these treatments remained within normal blood pressure ranges. These results support the potential of
pramlintide-containing combination treatments for
obesity.