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Diabetes Recombinant Human Insulins – Clinical Efficacy and Safety in Diabetes Therapy Wolfgang Landgraf 1 and Juergen Sandow 2 1. Medical Affairs Diabetes Division, Sanofi-Aventis Frankfurt, Germany; 2. Professor, Centre of Pharmacology, Johann-Wolfgang-Goethe University, Frankfurt/Main, Germany Abstract Insulin replacement therapy is the standard of care for patients with type 1 and advanced type 2 diabetes mellitus. Porcine and bovine pancreatic tissue was the source of the hormone for many years, followed by semisynthetic human insulin obtained by modification of animal insulin. With the development of recombinant DNA technology, recombinant (biosynthetic) human insulin became available in large amounts by biosynthesis in microorganisms (Escherichia coli, yeast) providing reliable supplies of the hormone worldwide at affordable costs. The purity and pharmaceutical quality of recombinant human insulin was demonstrated to be superior to animal and semisynthetic insulin and patients with diabetes could be safely and effectively transferred from animal or semisynthetic human insulin to recombinant human insulin with no change expected in insulin dose. The decision for change remains a clinical objective, follow-up after any change of insulin product is recommended to confirm clinical efficacy. This review provides a summary and retrospective assessment of early clinical studies with recombinant insulins (Insuman ® , Humulin ® , Novolin ® ). Keywords Recombinant human insulin, clinical studies, Insuman formulations, NPH insulin, premix insulins, review Disclosure: Wolfgang Landgraf is an employee of Sanofi-Aventis Germany. Juergen Sandow is a consultant to Sanofi Paris. Acknowledgements: Medical writing assistance for this manuscript was provided by Catherine Amey at Touch Medical Media and was funded by Sanofi US. The contents of this paper and opinions expressed within are those of the authors, and it was the decision of the authors to submit the manuscript for publication. The authors were responsible for the conception of the article and contributed to the writing, including critical review and editing of each draft, and approval of the submitted version. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: 22 July 2015 Accepted: 2 September 2015 Citation: European Endocrinology, 2016;12(1):12–7 Correspondence: Juergen Sandow, An der Linde 2, 61479 Glashütten, Germany. E: j-sandow@t-online.de Support: The publication of this article was supported by Sanofi US. Insulin preparations extracted from bovine or porcine pancreatic tissue have served as the mainstay of diabetes therapy since 1923, when commercial production was established in Europe and the US. 1 Animal insulin sources became a limiting factor to provide sufficient supply of insulin for the increasing clinical demand of insulin worldwide. When the molecular structure of human insulin was elucidated, attempts were made at total chemical synthesis but failed to provide a clinically relevant supply. 2,3 A next step towards obtaining clinically suitable human insulin was processing of animal insulin by exchange of amino acids and extensive purification. 4–6 The modified material was addressed as ‘semisynthetic human insulin’ and all pharmaceutical formulations (regular, neutral protamine Hagedorn [NPH], premixed insulins) were manufactured from such semisynthetic insulin. At the time when semisynthetic human insulin was introduced to the market, there was an intensive and partly acrimonious discussion about this change in insulin source and about the clinical relevance of the need for ‘human insulin’. When clinical studies confirmed the comparable efficacy of this new type of insulin, the discussion subsequently focused on the improvements related to further purification, in particular, in decreasing the formation of insulin- directed antibodies due to therapy, and reducing the risk of local and systemic allergic reactions. 12 ‘Recombinant human insulin’ became available in large amounts by recombinant DNA technology using fermentation in microorganisms (bacteria or yeast). Recombinant insulin has a superior level of purity and consistent quality compared with semisynthetic insulin. The process of biosynthesis was initially developed by Genentech and rapidly applied on an industrial scale by Eli Lilly, 2,6 followed by pharmaceutical and clinical process development at Novo Nordisk and Sanofi (formerly Hoechst AG/Hoechst Marion Roussel/Aventis). These companies are the lead manufacturers of recombinant human insulin (see Table 1), the human insulin profiles and clinical aspects have been described and reviewed extensively. 7–9 Since its first introduction to clinical therapy in 1982, recombinant human insulin represents the standard of care, 10–12 even after the introduction of insulin analogues. 12 The standard of care in diabetes therapy is addressed by international treatment guidelines. 10–12 Many clinical studies with recombinant human insulins submitted for regulatory approval have not been published in detail. Bioequivalence studies performed with recombinant Insuman ® (Sanofi, Paris, France) have been reported recently. 13 “Scientific Summaries and Public Assessment Reports” of the European Medicines Agency (EMA) for marketed human insulins including Insuman 14 are found at the EMA website, and approval information at the website of the US Food and Drug Administration (FDA). 15 TOU C H ME D ICA L ME D IA