Obesity is a global health concern due to the disturbing rise in prevalence and extent. With cardiovascular diseases being the lead cause of mortality in patients there is a substantial unmet medical need to develop novel drugs targeting not only obesity, but also obesity associated cardiovascular diseases such as hypertension and atherosclerosis. We hypothesize that combining the cardioprotective effects of adrenomedullin with the anti-obesity and glucoregulatory properties of amylin could be an effective treatment strategy. Here we show novel unimolecular peptide agonists with dual activity at both the amylin and adrenomedullin receptors. Using SPPS, a library of hybrid peptides was rationally designed by substituting amino acids essential for amylin activity into the native adrenomedullin sequence. The pharmacokinetic profile of the analogues was optimized by N-terminal lipidation with a C20 diacid. The functional activities of the analogues were assessed using a cAMP accumulation assay in cells overexpressing the human amylin receptor subtype 3 (hAMY3-R) or human adrenomedullin receptor subtype 1 (hAM1-R). All peptides were measured to be full agonists on both receptors. The hAMY3R potencies were equivalent to human amylin while potencies on the hAM1-R showed a range from equipotent to 100-fold less potent as compared to human adrenomedullin. Ongoing studies are aimed at addressing the efficacy and potency in rodent models of metabolic diseases. In summary we have designed, synthesized, and evaluated novel hybrid amylin-adrenomedullin peptide agonists with dual activity at the hAMY3R and hAM1-R for the potential treatment of obesity patients with high cardiovascular risk.