Reduced peripheral activity leading to hepato‐preferential action of basal insulin peglispro compared with insulin glargine in patients with type 1 diabetes

Mudaliar, Sunder; Henry, Robert R.; Ciaraldi, Theodore P.; Armstrong, Debra; Burke, P.; Pettus, Jeremy; Garhyan, Parag; Choi, Siak Leng; Knadler, Mary Pat; Lam, Eric Chen Quin; Prince, Melvin; Bose, Namrata; Pørksen, Niels; Sinha, Vikram; Linnebjerg, Helle; Jacober, Scott J.

doi:10.1111/dom.12753

Cited by 18 publications

(21 citation statements)

References 24 publications

(98 reference statements)

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“…Although conventional insulins suppress lipolysis, insulin clamp studies show that BIL suppresses lipolysis to a lesser degree than human insulin in dogs and compared to glargine in patients with T1D . Similar results were reported with the hepatopreferential insulin‐327 .…”

Section: Discussionsupporting

confidence: 73%

Different effects of basal insulin peglispro and insulin glargine on liver enzymes and liver fat content in patients with type 1 and type 2 diabetes

Cusi

Sanyal

Zhang

et al. 2016

Diabetes Obesity Metabolism

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Aims: To compare effects of basal insulin peglispro (BIL), a hepatopreferential insulin, to insulin glargine (glargine) on aminotransferases and liver fat content (LFC) in patients with type 1 and type 2 diabetes (T1D, T2D). Materials and Methods:Data from two Phase 2 and five Phase 3 randomized trials comparing BIL and glargine in 1709 T1D and 3662 T2D patients were integrated for analysis of liver laboratory tests. LFC, measured by magnetic resonance imaging (MRI) at baseline, 26 and 52 weeks, was analyzed in 182 T1D patients, 176 insulin-naïve T2D patients and 163 T2D patients previously treated with basal insulin.Results: Alanine aminotransferase (ALT) increased in patients treated with BIL, was higher than in glargine-treated patients at 4-78 weeks (difference at 52 weeks in both T1D and T2D: 7 international units/litre (IU/L), P < .001), and decreased after discontinuation of BIL. More BIL patients had ALT ≥3× upper limit of normal (ULN) than glargine. No patient had ALT ≥3× ULN with bilirubin ≥2× ULN that was considered causally related to BIL. In insulin-naїve T2D patients, LFC decreased with glargine but was unchanged with BIL. In T1D and T2D patients previously treated with basal insulin, LFC was unchanged with glargine but increased with BIL.In all three populations, LFC was higher after treatment with BIL vs glargine (difference at 52 weeks: 2.2% to 5.3%, all P < .01).Conclusions: Compared to glargine, patients treated with BIL had higher ALT and LFC at 52-78 weeks. No severe drug-induced liver injury was apparent with BIL treatment for up to 78 weeks.

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Section: Discussionsupporting

confidence: 73%

Different effects of basal insulin peglispro and insulin glargine on liver enzymes and liver fat content in patients with type 1 and type 2 diabetes

Cusi

Sanyal

Zhang

et al. 2016

Diabetes Obesity Metabolism

Self Cite

View full text Add to dashboard Cite

show abstract

“…Weight gain is commonly associated with insulin treatment, and previous studies have identified weight gain following GL treatment, but weight loss in T1DM patients treated with BIL . This difference may reflect the fact that BIL has attenuated peripheral effects compared to GL, resulting in a hepato‐preferential action . In Phase 3 studies, BIL, but not GL, increased triglycerides in T1DM patients, which may reflect less suppression of lipolysis by BIL in peripheral adipose tissue .…”

Section: Discussionsupporting

confidence: 93%

Basal insulin peglispro increases lipid oxidation, metabolic flexibility, thermogenesis and ketone bodies compared to insulin glargine in subjects with type 1 diabetes mellitus

Pørksen

Linnebjerg

Lam

et al. 2018

Diabetes Obesity Metabolism

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“…Increases in both K-18 and ALT with BIL were greater in previously insulin-treated patients with T2D in whom statistically significant increases in LFC (~5%) were observed 7 32. As previously reported,7 higher LFC with BIL versus glargine treatment may reflect the fact that BIL suppresses lipolysis to a lesser degree than glargine 44. Switching from an insulin that potently suppresses lipolysis (glargine) to one with a weaker effect on lipolysis (BIL) may result in increased flux of FFA to the liver that are esterified into hepatic triglyceride.…”

Section: Discussionmentioning

confidence: 67%

Cytokeratin-18 and Enhanced Liver Fibrosis Scores in Type 1 and Type 2 Diabetes and Effects of Two Different Insulins

Sanyal

Cusi

Hartman

et al. 2018

Journal of Investigative Medicine

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Data on cytokeratin-18 (K-18) and enhanced liver fibrosis (ELF) score in insulin-treated diabetes patients with non-alcoholic fatty liver disease (NAFLD) are limited. This study analyzed phase III data comparing basal insulin peglispro (BIL) and insulin glargine in type 1 (T1D), and type 2 diabetes (T2D) (insulin-naïve and insulin-treated). Alanine aminotransferase (ALT), K-18, ELF scores and liver fat content (LFC), measured by MRI, were obtained longitudinally. Baseline K-18 (U/L) was higher in T2D (range: 207‒247) than T1D (range: 148‒183), correlated with ALT in all populations (r (range) 0.264‒0.637, p<0.05), but with LFC only in T2D (r (range) 0.474‒0.586, p<0.05). K-18 increased significantly from baseline in BIL-treated, but not glargine-treated patients. Change from baseline (CFB) K-18 was significantly correlated with CFB in ALT in BIL-treated T2D populations. Baseline ELF scores were higher in T2D (range: 9.12‒9.20) than T1D (range: 8.24‒8.36), correlated with ALT in T1D only (0.209, p<0.05), and not correlated with LFC in any population. ELF scores increased significantly from baseline in BIL-treated but not glargine-treated patients. There were no correlations between CFB in LFC and ELF score at week 52 in any treatment group/population. In all BIL-treated populations, CFB in ALT and CFB in ELF score at week 52 were positively correlated. These data characterize associations of K-18 and ELF score with ALT and LFC in insulin-treated patients with T1D and T2D. Hepatopreferential insulins may be associated with increased K-18 and ELF scores but mechanisms and clinical significance are unknown. ClinicalTrials.gov identifiers are NCT01481779, NCT01435616, NCT01454284 and NCT01582451.

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Reduced peripheral activity leading to hepato‐preferential action of basal insulin peglispro compared with insulin glargine in patients with type 1 diabetes

Cited by 18 publications

References 24 publications

Different effects of basal insulin peglispro and insulin glargine on liver enzymes and liver fat content in patients with type 1 and type 2 diabetes

Different effects of basal insulin peglispro and insulin glargine on liver enzymes and liver fat content in patients with type 1 and type 2 diabetes

Basal insulin peglispro increases lipid oxidation, metabolic flexibility, thermogenesis and ketone bodies compared to insulin glargine in subjects with type 1 diabetes mellitus

Cytokeratin-18 and Enhanced Liver Fibrosis Scores in Type 1 and Type 2 Diabetes and Effects of Two Different Insulins

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