Lipid changes during basal insulin peglispro, insulin glargine, or <scp>NPH</scp> treatment in six <scp>IMAGINE</scp> trials

Ginsberg, Henry N.; Cariou, Bertrand; Orchard, Trevor J.; Chen, Lei; Luo, Junxiang; Bastyr, Edward J.; Bue-Valleskey, Juliana M.; Chang, Annette M.; Iványi, T.; Jacober, Scott J.; Hoogwerf, Byron J.

doi:10.1111/dom.12754

Cited by 18 publications

(36 citation statements)

References 22 publications

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“…Patients treated with glargine had no change in mean LFC, while patients treated with BIL had a mean increase in LFC [LSM difference at 52 weeks: 2.20% (1.26–3.13%); p < 0.001] (Additional file 1: Table S1) [8]. Positive correlations with changes in LFC were found for changes in medium HDL, large VLDL, and VLDL size, but only large VLDL in the glargine group correlated significantly (Table 3).…”

Section: Resultsmentioning

confidence: 99%

“…Mean LFC did not change in the glargine group, but increased from baseline in the BIL group [LSM difference at 52 weeks: 5.27% (3.43–7.11%); p < 0.001] (Additional file 1: Table S1) [8]. Some correlations were found for changes in lipoprotein parameters with changes in LFC in patients taking BIL (Table 3).…”

Section: Resultsmentioning

confidence: 99%

“…Data from the Phase 3 clinical program for BIL—compared to insulin glargine or NPH—have also recently been reported [8]. However, the effects of insulin therapies on NMR-determined lipoprotein subclasses is limited to selected cohorts of patients with type 1 diabetes [19–24] and very small studies in type 2 diabetes [25–29].…”

Section: Discussionmentioning

confidence: 99%

“…In patients previously on basal insulin and randomized to BIL in Phase 2 studies, an increase from baseline in serum TGs was noted [6, 7]. In the Phase 3 program, serial lipid profiles were obtained to further characterize and understand the time course for the potential changes in lipid metabolism in response to BIL [8]. In the overall BIL program at baseline, patients with type 2 diabetes on insulin had nominally lower TG values (mean range 144–149 mg/dL) than insulin naïve patients with type 2 diabetes (mean range 159–161 mg/dL); patients with type 1 diabetes had lower TG values (mean range 83–91 mg/dL) than patients with type 2 diabetes.…”

Section: Introductionmentioning

confidence: 99%

“…The primary LFC and routine blood lipid results are reported elsewhere [8, 11]. Here we report the results of the lipoprotein particle and related lipid analyses by cohort (type 1 diabetes, type 2 insulin naïve, or type 2 previously on insulin) and treatment (insulin glargine or BIL) at baseline and follow-up.…”

Section: Introductionmentioning

confidence: 99%

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The effects of basal insulin peglispro vs. insulin glargine on lipoprotein particles by NMR and liver fat content by MRI in patients with diabetes

Orchard

Cariou

Connelly

et al. 2017

Cardiovasc Diabetol

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BackgroundIn Phase 2/3 studies of basal insulin peglispro (BIL) compared to insulin glargine, patients with type 1 or type 2 diabetes previously treated with insulin and randomized to BIL had an increase in serum triglycerides (TGs). To further understand lipoprotein changes, a lipid substudy which included liver fat content was designed to assess relationships among the measured variables for each diabetes cohort and compare the hepato-preferential insulin BIL to glargine.MethodsIn three cohorts of patients with diabetes (type 1, type 2 insulin naïve, and type 2 previously on insulin; n = 652), liver fat content (LFC) was determined by magnetic resonance imaging (MRI) and blood lipids were analyzed by nuclear magnetic resonance (NMR) spectroscopy at baseline, 26 and 52 weeks of treatment. Apolipoproteins, adiponectin, and other lipid parameters were also measured. Descriptive statistics were done, as well as correlation analyses to look for relationships among LFC and lipoproteins or other lipid measures.ResultsIn patients with type 1 diabetes treated with BIL, but not glargine, small LDL and medium and large VLDL subclass concentrations increased from baseline. In patients with type 2 diabetes previously on insulin and treated with BIL, large VLDL concentration increased from baseline. In insulin naïve patients with type 2 diabetes treated with BIL, there were very few changes, while in those treated with glargine, small LDL and large VLDL decreased from baseline. Baseline LFC correlated significantly in one or more cohorts with baseline large VLDL, small LDL, VLDL size, and Apo C3. Changes in LFC by treatment showed generally weak correlations with lipoprotein changes, except for positive correlations with large VLDL and VLDL size. Adiponectin was higher in patients with type 1 diabetes compared to patients with type 2 diabetes, but decreased with treatment with both BIL and glargine.ConclusionsThe lipoprotein changes were in line with the observed changes in serum TGs; i.e., the cohorts experiencing increased TGs and LFC with BIL treatment had decreased LDL size and increased VLDL size. These data and analyses add to the currently available information on the metabolic effects of insulins in a very carefully characterized cohort of patients with diabetes. Clinicaltrials.gov registration numbers and dates NCT01481779 (2011), NCT01435616 (2011), NCT01454284 (2011), NCT01582451 (2012)Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-017-0555-1) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The effects of basal insulin peglispro vs. insulin glargine on lipoprotein particles by NMR and liver fat content by MRI in patients with diabetes

Orchard

Cariou

Connelly

et al. 2017

Cardiovasc Diabetol

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The past, present, and future of basal insulins

Pettus

Cavaiola

Tamborlane

et al. 2015

Diabetes Metabolism Res

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Insulin production by the pancreas follows a basic pattern where basal levels of insulin are secreted during fasting periods, with prandial increases in insulin associated with food ingestion. The aim of insulin therapy in patients with diabetes is to match the endogenous pattern of insulin secretion as closely as possible without causing hypoglycaemia. There are several optimal pharmacokinetic and pharmacodynamic properties of long-acting basal insulins that can help to achieve this aim, namely, as follows: activity that is flat and as free of peaks as possible, a duration of action of ≥24-h, and as little day-to-day variation as possible. The long-acting basal insulins are a fundamental therapy for patients with type 1 and type 2 diabetes, and those that are currently available have many benefits; however, the development of even longer-acting insulins and improved insulin delivery techniques may lead to better glycemic control for patients in the future. Established long-acting basal insulins available in the United States and Europe include insulin glargine 100 units/mL and insulin detemir, both of which exhibit similar glycemic control to that of the intermediate-acting neutral protamine Hagedorn insulin, but with a reduction in hypoglycaemia. Newer insulin products available include new insulin glargine 300 units/mL (United States and Europe) and the ultra-long-acting insulin degludec (Europe) with basal insulin peglispro currently in development. These new insulins demonstrate different pharmacokinetic/pharmacodynamic profiles and longer durations of action (>24 h) compared with insulin glargine 100 units/mL, which may lead to potential benefits. The introduction of biosimilar insulins may also broaden access to insulins by reducing treatment costs. Copyright © 2015 John Wiley & Sons, Ltd.

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How Can a Good Idea Fail? Basal Insulin Peglispro [LY2605541] for the Treatment of Type 2 Diabetes

2016

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IntroductionLack of control in diabetic patients has stimulated the development of new insulin analogues. One of these was basal insulin peglispro (BIL) or LY2605541; it had a large hydrodynamic size, flat pharmacokinetic profile, half life of 2–3 days and acted preferably in the liver.MethodsWe reviewed the recent literature examining the pharmacokinetics, pharmacodynamics, efficacy and safety of BIL treatment in type 2 diabetes patients.ResultsThe pharmacodynamic and pharmacokinetic outline of BIL seemed to have an advantage over neutral protamine Hagedorn and glargine insulins. Recently, phase 3 studies suggested BIL was superior to glargine in reducing glucose levels in type 1 and type 2 diabetes patients in addition to causing less weight gain. It showed a different hypoglycaemia rate profile depending on the study population, with less nocturnal hypoglycaemia compared to glargine. Unfortunately, it caused higher transaminase and triglyceride levels, which led the company to discontinue development. The decision came after it had been analysed by the regulatory authorities and other external experts concerning the worse liver profile data from the IMAGINE trials.ConclusionsBIL was an adequate basal insulin analogue with interesting specific properties. Unfortunately the disadvantages as shown in the lipid values and liver function tests led to its failure.

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Lipid changes during basal insulin peglispro, insulin glargine, or NPH treatment in six IMAGINE trials

Cited by 18 publications

References 22 publications

The effects of basal insulin peglispro vs. insulin glargine on lipoprotein particles by NMR and liver fat content by MRI in patients with diabetes

The effects of basal insulin peglispro vs. insulin glargine on lipoprotein particles by NMR and liver fat content by MRI in patients with diabetes

The past, present, and future of basal insulins

How Can a Good Idea Fail? Basal Insulin Peglispro [LY2605541] for the Treatment of Type 2 Diabetes

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