Box 1. Drug Summary.
| Drug name | Pramlintide acetate | Metreleptin (Recombinant-methionyl human leptin) |
| Phase | FDA approved, March 2005 | In Phase III |
| Indication | Type 1 diabetes: Maintenance dose of 30 or 60
(as tolerated) titrated from a dose of 15 mg Insulin-Using Type 2 diabetes: Maintenance dose of 120 μg (as tolerated) titrated from a dose of 60 |
Congenital leptin deficiency, lipodystrophy, hypothalamic amenorrhea and leptin replacement therapy for weight maintenance |
| Pharmacology description | In clinical studies in patients with
insulin-using type 2 and type 1 diabetes, pramlintide administration
resulted in a reduction in mean postprandial glucose concentrations,
reduced glucose fluctuations, and reduced food intake Peak: 15 min [50] Half-life: 20 - 50 min [50,51] |
Based on results of nonclinical and clinical
studies, the mechanisms of action of metreleptin include the
following: • Correction of hyperphagia secondary to leptin deficiency and the concomitant reduction in caloric and fat intake [52,53] • Stimulation of fatty acid oxidation throughout the body and lowering of plasma, hepatic and myocellular lipid levels resulting in increased insulin sensitivity and improved glycemic control [54-61] • Improvement in insulin suppression of glucose production in the liver and increase in insulin-stimulated peripheral glucose uptake in the muscle [20,54,62] Therefore, leptin acts via multiple mechanisms to decrease triglyceride and other lipid intermediates in lipodystrophy patients, reducing their accumulation in tissues such as liver and muscle, and ameliorating severe insulin resistance, thereby improving hyperglycemia and hypertriglyceridemia Peak: 4 h [63] Half-life: 2 - 5h [63,64] |
| Route of administration | Administered subcutaneously into thigh or abdomen separate from site of insulin injection immediately before major meals (≥ 250 kcal or ≥ 30 g carbohydrate) | Administered subcutaneously into the abdomen |
| Chemical structure | Lys-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln- Arg-Leu-Ala-Asn-Phe-Leu-Val-His-Ser-Ser- Asn-Asn-Phe-Gly-Pro-Ile-Leu-Pro-Pro-Thr- Asn-Val-Gly-Ser-Asn-Thr-Tyr-NH2 acetate (salt) with a disulfide bridge between the two Cys residues [65] |
NH2-Met-Val-Pro-Ile-Gln-Lys-Val-Gln-Asp-Asp-Thr-Lys- Thr-Leu-Ile-Lys-Thr-Ile-Val-Thr-Arg-Ile-Asn-Asp-Ile-Ser- His-Thr-Gln-Ser-Val-Ser-Ser-Lys-Gln-Lys-Val-Thr-Gly-Leu- Asp-Phe-Ile-Pro-Gly-Leu-His-Pro-Ile-Leu-Thr-Leu-Ser-Lys- Met-Asp-Gln-Thr-Leu-Ala-Val-Tyr-Gln-Gln-Ile-Leu-Thr- Ser-Met-Pro-Ser-Arg-Asn-Val-Ile-Gln-Ile-Ser-Asn-Asp- Leu-Glu-Asn-Leu-Arg-Asp-Leu-Leu-His-Val-Leu-Ala-Phe- Ser-Lys-Ser-Cys-His-Leu-Pro-Trp-Ala-Ser-Gly-Leu-Glu- Thr-Leu-Asp-Ser-Leu-Gly-Gly-Val-Leu-Glu-Ala-Ser-Gly- Tyr-Ser-Thr-Glu-Val-Val-Ala-Leu-Ser-Arg-Leu-Gln-Gly- Ser-Leu-Gln-Asp-Met-Leu-Trp-Gln-Leu-Asp-Leu-Ser-Pro- Gly-Cys-COOH |
| Pivotal trial(s) | Type 1 diabetes: [66-68] Type 2 diabetes: [69-71] |
Congenital leptin deficiency [18] Lipodystrophy: [20] Hypothalamic amenorrhea: [22] Obesity: [26,48] Weight maintenance: [38] |