IntroductionThe aim of this analysis was to estimate the cost of insulin-related hypoglycemia in adult patients with diabetes in Italy using the Local Impact of Hypoglycemia Tool (LIHT), and to explore the effect of different hypoglycemia rates on budget impact.MethodsDirect costs and healthcare resource utilization were estimated for severe and non-severe hypoglycemic episodes in Italy and applied to the population of adults with type 1 diabetes (T1DM) and type 2 diabetes (T2DM) and their corresponding hypoglycemia episode rates (0.49 severe and 53.3 non-severe episodes per year for T1DM, and 0.09 severe and 9.3 non-severe episodes per year for T2DM). Uncertainty around model inputs was explored through sensitivity and scenario analyses.ResultsThe direct cost of insulin-related hypoglycemia in Italy is estimated at €144.7 million per year, with €65 million attributable to severe episodes and €79.6 million due to non-severe episodes. The total cost of hypoglycemia is approximately 1.7-fold higher for T2DM (€91.7 million) than for T1DM (€53 million). The cost of a hypoglycemic episode ranges from €4.59 for a non-severe event where additional self-monitoring of blood glucose (SMBG) testing is the only cost incurred, to €5790.59 for a severe event that also requires an ambulance, A&E, hospitalization, and a visit to a diabetes specialist. A reduction in hypoglycemia event rates could result in substantial cost savings; for example, a 20% reduction in severe and non-severe hypoglycemia rates could result in a saving of €47,769 per general population of 100,000 people.ConclusionsThe LIHT highlights the substantial economic burden of insulin-related hypoglycemia in Italy, particularly with regards to non-severe hypoglycemia, an aspect of hypoglycemia that is often overlooked. This analysis may aid healthcare decision-making by allowing the costs of insulin therapies or diabetes self-management programs to be balanced with the savings provided by reductions in hypoglycemia.FundingNovo Nordisk, UK.Electronic supplementary materialThe online version of this article (10.1007/s13300-018-0418-0) contains supplementary material, which is available to authorized users.