Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • GLP and glucose dependent insulinotropic

    2021-11-23

    GLP-1 and glucose-dependent insulinotropic peptide (GIP) are gut hormones secreted from intestinal L fk866 and K cells, respectively. Together, these hormones account for the vast majority of the incretin effect, the enhanced postprandial insulin secretion observed in healthy adults (Dupre et al., 1973, Kreymann et al., 1987, McIntyre et al., 1964, Nauck et al., 1986). Though inhibition of dipeptidyl peptidase 4 (DPP-4) increases levels of both active GLP-1 and GIP, suggesting a common pharmacological end goal, the majority of clinical research pertaining to the therapeutic use of incretins has thus far focused on GLP-1 with much less attention given to GIP (Baggio and Drucker, 2007). The historical emphasis on GLP-1 therapy arose partly due to the early positive clinical results achieved with GLP-1RAs (Gutniak et al., 1992, Nauck et al., 1996) and partly due to reports in animals that GIP promoted obesity and impaired lipid metabolism (Gault et al., 2002, Gault et al., 2005, Irwin et al., 2004, McClean et al., 2007, Miyawaki et al., 2002). Additionally, single-dose trials in patients with T2D reported that GIP worsened postprandial hyperglycemia and deepened the conviction that GIP agonism may not have therapeutic benefit (Chia et al., 2009, Mentis et al., 2011, Nauck et al., 1993, Vilsbøll et al., 2002). The diabetic state is characterized by a complex array of progressive changes, to both the diabetic pancreas and, consequently, the entero-insular axis, notably manifesting in hyperglycemia, reduced β cell mass, and diminished incretin effect (Campbell and Drucker, 2013, Nauck and Meier, 2016). The incretin effect of GIP in patients with T2D is blunted primarily as a consequence of hyperglycemia rather than being a causal defect (Knop et al., 2007a, Knop et al., 2007b). This can be seen experimentally in patients with T2D who regain some GIP sensitivity after approaching normoglycemia with insulin therapy or treatment with DPP-4 inhibitors (Aaboe et al., 2015, Højberg et al., 2009). This requirement for glycemic control affects the interpretation of previous trials assessing acute GIP administration, suggesting that chronic therapy in well-controlled patients could result in different outcomes. Recent data suggest that GIP may regulate β cell survival through signaling pathways independent of GLP-1, supporting the hypothesis that the two incretins are not redundant and may complement one another (Campbell et al., 2016). The pharmacological integration of the activities of both incretins could conceivably function in two stages where GLP-1RA establishes glycemic control, reduces body weight, and sets the foundation upon which glucose-dependent insulinotropic peptide receptor agonists (GIP-RA) can further improve metabolism and body weight. The selectively engineered peptides intermixing balanced, potent GLP-1 and GIP agonism have demonstrated, in sustained administration in rodents and non-human primates, their ability to further decrease blood glucose and body weight when compared with peptides functioning by just one of the two mechanisms (Finan et al., 2013). NNC0090-2746 (previously developed as RG7697) is a fatty-acylated GIP/GLP-1 dual agonist in clinical development for the treatment of T2D. It exhibits balanced activity for the human GLP-1 (EC50 = 5 pM) and GIP (EC50 = 3 pM) receptors, with virtually no meaningful agonism at any other related receptor (EC50 at glucagon receptor of >1 μM) (Finan et al., 2013). Recent phase 1 trials of NNC0090-2746 have shown that steady-state concentration of the peptide is achieved within 1 week by daily dosing of patients with T2D (Schmitt et al., 2017). Once-daily doses of up to 2 mg were well tolerated, with gastrointestinal (GI) adverse effects of the type typically observed with GLP-1RAs increasingly evident at higher doses (Portron et al., 2017). Reductions in fasting, postprandial, and 24-hr profile plasma glucose were observed after 2 weeks of treatment at doses ≥0.75 mg and were associated with decreases in HbA1c (up to 0.67% [absolute change]) (Schmitt et al., 2017). Building upon these clinical observations, we present here a phase 2a clinical trial of NNC0090-2746 in patients with T2D inadequately controlled with metformin.