A Fixed Ratio Combination of Insulin Degludec and Liraglutide (IDegLira) Reduces Glycemic Fluctuation and Brings More Patients with Type 2 Diabetes Within Blood Glucose Target Ranges.

BACKGROUND: Reducing glycemic fluctuation is important for optimal diabetes management. This post hoc analysis examined glycemic fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone. METHODS: We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients with type 2 diabetes (T2D), and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess glycemic fluctuation and day-to-day variability. RESULTS: Compared with IDeg, IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (3.9-9.0 mmol/L) than IDeg for all pre- and postprandial values, and for the full nine-point profile (P < 0.05 for all). IDegLira also resulted in a greater reduction in the range of SMBG values over 24 h than IDeg (P ≤ 0.0001). CGM data showed that IDegLira provided greater reductions in interstitial glucose (IG) fluctuation (P = 0.0018) and postprandial IG increment (P = 0.0288) compared with IDeg. Compared with liraglutide, IDegLira brought a higher proportion of subjects within SMBG target ranges (all pre- and all postprandial values, and the full nine-point profile, P < 0.01 for all) and resulted in a greater reduction of time outside the IG target range (P = 0.0072). IDegLira also reduced mean IG more than liraglutide (P < 0.0001). CONCLUSIONS: Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than either IDeg or liraglutide alone.

Contribution of liraglutide in the fixed-ratio combination of insulin degludec and liraglutide (IDegLira).

OBJECTIVE: Insulin degludec/liraglutide (IDegLira) is a novel combination of insulin degludec (IDeg) and liraglutide. This trial investigated the contribution of the liraglutide component of IDegLira versus IDeg alone on efficacy and safety in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: In a 26-week, double-blind trial, patients with type 2 diabetes (A1C 7.5-10.0% [58-86 mmol/mol]) on basal insulin (20-40 units) and metformin with or without sulfonylurea/glinides were randomized (1:1) to once-daily IDegLira + metformin or IDeg + metformin with titration aiming for fasting plasma glucose between 4 and 5 mmol/L. Maximum allowed doses were 50 dose steps (equal to 50 units IDeg plus 1.8 mg liraglutide) and 50 units for IDeg. The primary end point was change in A1C from baseline. RESULTS: A total of 413 patients were randomized (mean A1C 8.8% [73 mmol/mol]; BMI 33.7 kg/m2). IDeg dose, alone or as part of IDegLira, was equivalent (45 units). A1C decreased by 1.9% (21 mmol/mol) with IDegLira and by 0.9% (10 mmol/mol) with IDeg (estimated treatment difference -1.1% [95% CI -1.3, -0.8], -12 mmol/mol [95% CI -14, -9; P < 0.0001). Mean weight reduction with IDegLira was 2.7 kg vs. no weight change with IDeg, P < 0.0001. Hypoglycemia incidence was comparable (24% for IDegLira vs. 25% for IDeg). Overall adverse events were similar, and incidence of nausea was low in both groups (IDegLira 6.5% vs. IDeg 3.5%). CONCLUSIONS: IDegLira achieved glycemic control superior to that of IDeg at equivalent insulin doses without higher risk of hypoglycemia and with the benefit of weight loss. These findings establish the efficacy and safety of IDegLira and the distinct contribution of the liraglutide component.

Pharmacokinetics and pharmacodynamics of growth hormone in patients on chronic haemodialysis compared with matched healthy subjects: an open, nonrandomized, parallel-group trial.

BACKGROUND: GH may be beneficial in treating patients with end-stage renal disease (ESRD). However, the efficacy and safety of GH could be compromised by the potential for accumulation in the circulation. OBJECTIVE: The objective was to investigate the pharmacokinetics and safety of GH treatment in ESRD patients. DESIGN: This was an open, nonrandomized, single-centre parallel-group study lasting 8-9 days. SUBJECTS: Eleven adult ESRD patients and 10 matched healthy individuals received recombinant human GH (50 microg/kg/day for 7 days) by subcutaneous injection; there were two dose reductions (25%) from Day 5/7. ESRD patients underwent dialysis four times. MEASUREMENTS: Serum concentrations of GH, insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-I (IGFBP-I), IGFBP-III and GHBP were measured. The primary end-point was GH exposure [area-under-the-curve (AUC) calculated from the 24-h profile] on Days 7-8. RESULTS: GH AUC(0-24 h) was greater for patients (387.91 +/- 134.13 microg h/l) than healthy subjects (225.35 +/- 59.63 microg h/l) and the 90% confidence interval (CI) for the estimated patient : healthy subject ratio (1.40-2.07) was not within the acceptance interval (0.67-1.50). GH AUC(18-24 h) for patients and healthy subjects (3.03 +/- 2.71 microg h/l and 6.37 +/- 4.21 microg h/l) returned approximately to baseline (2.86 +/- 3.91 microg h/l and 1.09 +/- 1.43 microg h/l); terminal half-life (t(1/2,z)) was shorter for patients (2.28 +/- 00.43 h vs. 3.23 +/- 00.75 h). No major safety issues were identified. CONCLUSIONS: Results demonstrate a difference between patients and healthy subjects regarding GH AUC(0-24 h). However, GH concentrations for both groups were comparable to baseline by 20-22 h, thus GH was not retained in the circulation of ESRD patients.

Recombinant factor VIIa in patients with coagulopathy secondary to anticoagulant therapy, cirrhosis, or severe traumatic injury: review of safety profile.

BACKGROUND: In recent years, the hemostatic agent recombinant factor VIIa (rFVIIa) has emerged as a potentially new therapeutic agent for management of coagulopathy in patients with cirrhosis or following severe traumatic injury, a complex problem for clinicians in which standard treatment strategies are not always effective. As with other hemostatic agents, a primary safety concern of rFVIIa therapy is the theoretical possibility that systemic administration could confer an increased risk of thrombotic complications. So far, clinical experience indicates rFVIIa to be a safe treatment for currently approved indications within hemophilia. Little information is available, however, for patient populations outside this clinical setting. STUDY DESIGN AND METHODS: This article reviews critical safety data obtained from 13 Novo Nordisk-sponsored clinical trials of rFVIIa in patients with coagulopathy secondary to anticoagulant therapy, cirrhosis, or severe traumatic injury. RESULTS: Thrombotic adverse events were reported for 5.3 percent (23/430) of placebo-treated patients and 6.0 percent (45/748) of patients on active treatment. No significant difference was found between placebo-treated and rFVIIa-treated patients with respect to the incidence of thrombotic AEs, either on an individual trial basis or for these trial populations combined (p=0.57). CONCLUSION: An important determinant for the safety profile reported here is likely to be the specific mechanism of action of rFVIIa, shown in experimental studies to be localized to the site of vascular injury where tissue factor is exposed.