Hepatic-directed insulin utilizes a hepatocyte-targeting moiety passively attaching free insulin, improving subcutaneous insulin’s hepatic biodistribution. We assessed injections of HDV-insulin lispro (HDV-L) vs. insulin lispro (LIS) in T1DM in a 26-week, multicenter, randomized, double-blind trial of 176 subjects (randomized 2:1 HDV-L:LIS) with A1C 7.0-10.5% treated with basal insulin glargine or degludec. Primary objective was HDV-L A1C non-inferiority (prespecified margin 0.4%). Mean A1C change to week 26 was -0.09% (HDV-L) and -0.16% (LIS), (estimated treatment difference, HDV-L - LIS: +0.09% [95% CI -0.18 to 0.35]), confirming HDV-L non-inferiority. A1C status modified treatment group effect on “severe” hypoglycemia (subjectively categorized by investigators as “mild,” “moderate,” “severe,” or “life threatening”) incidence (interaction p-value <.001), with less hypoglycemia in HDV-L vs. LIS in poor control but more hypoglycemia in HDV-L with better control. Thus, further analyses used subgroups (A1C ≥8.5% vs. <8.5%). HDV-L treated subjects ≥8.5% A1C reported less “severe” hypoglycemia than LIS (69 vs. 97/100 person-years, p=.03), and % time <54 mg/dL during week 26 trended lower (median 0.7% vs. 2.6%, p=.09). Conversely, with baseline A1C <8.5%, more “severe” hypoglycemia was reported with HDV-L (191 vs. 21, p=0.001), and time <54 mg/dL during week 26 trended higher (median 2.0% vs. 0.6%, p=0.16). All subjects showed similar A1C change for both treatments but HDV-L subjects with A1C≥8.5% improved A1C with ~25% less bolus insulin (p=0.02) but comparable basal (p=0.37) at endpoint. HDV-L and LIS subjects with A1C <8.5% both showed little difference in bolus/basal dosages at endpoint (p=0.86 and 0.90). Favorable total cholesterol change with HDV-L (-6.5 mg/dL) vs. LIS (+7.3 mg/dL) was seen (p<.01). No hepatic safety signals were identified. We conclude that of HDV-L is non-inferior to LIS and its liver-targeted component potentiates insulin effect.


D.C. Klonoff: Consultant; Self; EOFlow, Lifecare, Inc., Merck & Co., Inc., Novo Nordisk A/S, Roche Diagnostic USA, Voluntis USA. B.W. Bode: Consultant; Self; ADOCIA, Lexicon Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; Becton, Dickinson and Company, Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Eyenuk Inc., Insulet Corporation, National Institutes of Health, Novo Nordisk Inc., Sanofi Research & Development, Senseonics, Xeris Pharmaceuticals, Inc. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi US, Senseonics. Stock/Shareholder; Self; AgaMatrix, Glytec, LLC. N.J. Cohen: None. W. Geho: Board Member; Self; Diasome Pharmaceuticals, Inc. D.B. Muchmore: Consultant; Self; ADOCIA, Capillary Biomedical, Inc., Diasome Pharmaceuticals, Inc., Zucara Therapeutics Inc. Stock/Shareholder; Self; Capillary Biomedical, Inc., Diasome Pharmaceuticals, Inc.



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