Switching from sitagliptin to liraglutide to manage patients with type 2 diabetes in the UK: A long-term cost-effectiveness analysis.

AIMS: The recent LIRA-SWITCH trial showed that switching from sitagliptin 100 mg to liraglutide 1.8 mg led to statistically significant and clinically relevant improvements in glycated haemoglobin (HbA1C) and body mass index (BMI). Based on these findings, the aim of the present study was to assess the long-term cost-effectiveness of switching from sitagliptin to liraglutide in patients with type 2 diabetes in the UK. MATERIALS AND METHODS: The IQVIA CORE Diabetes Model Version 8.5+ was used to project costs and clinical outcomes over patients' lifetimes. Baseline cohort characteristics and treatment effects were derived from the LIRA-SWITCH trial. Future costs and clinical benefits were discounted at 3.5% annually. Costs were accounted in pounds sterling (GBP) and expressed in 2016 values. One-way and probabilistic sensitivity analyses were performed. RESULTS: Model projections showed improved quality-adjusted life expectancy for patients with poorly controlled HbA1c upon switching from sitagliptin to liraglutide, compared with continuing sitagliptin treatment (9.18 vs 9.02 quality-adjusted life years [QALYs]). Treatment switching was associated with increased overall costs (GBP 24737 vs GBP 22362). Higher pharmacy costs were partially offset by reduced diabetes-related complication costs in patients who switched to liraglutide. Switching to liraglutide was associated with an incremental cost-effectiveness ratio of GBP 15423 per QALY gained vs continuing with sitagliptin treatment. CONCLUSIONS: Switching from sitagliptin 100 mg to liraglutide 1.8 mg in patients with poor glycaemic control was projected to improve clinical outcomes and is likely to be considered cost-effective in the UK setting and, therefore, a good use of limited NHS resources.

Unique posttranslational modifications in eukaryotic translation factors and their roles in protozoan parasite viability and pathogenesis.

Protozoan parasites are one of the major causes of diseases worldwide. The vector transmitted parasites exhibit complex life cycles involving interactions between humans, protozoa, and arthropods. In order to adapt themselves to the changing microenvironments, they have to undergo complex morphological and metabolic changes. These changes can be brought about by expressing a new pool of proteins in the cell or by modifying the existing repertoire of proteins via posttranslational modifications (PTMs). PTMs involve covalent modification and processing of proteins thereby modulating their functions. Some of these changes may involve PTMs of parasite proteins to help the parasite survive within the host and the vector. Out of many PTMs known, three are unique since they occur only on single proteins: ethanolamine phosphoglycerol (EPG) glutamate, hypusine and diphthamide. These modifications occur on eukaryotic elongation factor 1A (eEF1A), eukaryotic initiation factor 5A (eIF5A) and eukaryotic elongation factor 2 (eEF2), respectively. Interestingly, the proteins carrying these unique modifications are all involved in the elongation steps of translation. Here we review these unique PTMs, which are well conserved in protozoan parasites, and discuss their roles in viability and pathogenesis of parasites. Characterization of these modifications and studying their roles in physiology as well as pathogenesis will provide new insights in parasite biology, which may also help in developing new therapeutic interventions.

A unique modification of the eukaryotic initiation factor 5A shows the presence of the complete hypusine pathway in Leishmania donovani.

Deoxyhypusine hydroxylase (DOHH) catalyzes the final step in the post-translational synthesis of an unusual amino acid hypusine (N(€)-(4-amino-2-hydroxybutyl) lysine), which is present on only one cellular protein, eukaryotic initiation factor 5A (eIF5A). We present here the molecular and structural basis of the function of DOHH from the protozoan parasite, Leishmania donovani, which causes visceral leishmaniasis. The L. donovani DOHH gene is 981 bp and encodes a putative polypeptide of 326 amino acids. DOHH is a HEAT-repeat protein with eight tandem repeats of α-helical pairs. Four conserved histidine-glutamate sequences have been identified that may act as metal coordination sites. A ~42 kDa recombinant protein with a His-tag was obtained by heterologous expression of DOHH in Escherichia coli. Purified recombinant DOHH effectively catalyzed the hydroxylation of the intermediate, eIF5A-deoxyhypusine (eIF5A-Dhp), in vitro. L. donovani DOHH (LdDOHH) showed ~40.6% sequence identity with its human homolog. The alignment of L. donovani DOHH with the human homolog shows that there are two significant insertions in the former, corresponding to the alignment positions 159-162 (four amino acid residues) and 174-183 (ten amino acid residues) which are present in the variable loop connecting the N- and C-terminal halves of the protein, the latter being present near the substrate binding site. Deletion of the ten-amino-acid-long insertion decreased LdDOHH activity to 14% of the wild type recombinant LdDOHH. Metal chelators like ciclopirox olamine (CPX) and mimosine significantly inhibited the growth of L. donovani and DOHH activity in vitro. These inhibitors were more effective against the parasite enzyme than the human enzyme. This report, for the first time, confirms the presence of a complete hypusine pathway in a kinetoplastid unlike eubacteria and archaea. The structural differences between the L. donovani DOHH and the human homolog may be exploited for structure based design of selective inhibitors against the parasite.