Subgroup analysis showed that patients with relatively lower
Subgroup analysis showed that patients with relatively lower CrCl levels (>50–80 mL/min) were more likely to initiate treatment on a lower dose (17% for all DPP-4 inhibitors; 22% excluding linagliptin). Nevertheless, even in patients with higher CrCl value (>80–120 mL/min and >120 mL/min), at least 10% were prescribed a dose lower than that specified in the SPC ().
Patients with CrCl >50 ml/min initiating on lower than the SPC specified DPP-4 inhibitor dose were similar comparing to patients initiating on the SPC specified dose in terms of last Hba1c before or at DPP-4 inhibitor initiation (8.8 vs 9.0 %), last BMI before or at DPP-4 inhibitor initiation (32.2 vs 32.7 kg/m2) and were approximately 2 years older at DPP-4 inhibitor initiation (63.2 vs 60.9).
Conclusions First, it should be noted that even though non-linagliptin DPP-4 inhibitor SPCs specified thresholds for dose adjustment in CrCl via the use of the Cockcroft-Gault formula at the time of the patients’ treatment, in January 2018, the sitagliptin SPC was changed to include glomerular TC-H 106 rate (GFR) thresholds to define dose adjustment requirements. The National Institute for Health and Care Excellence national guidelines also recommend that clinical laboratories report an estimated GFR using the Chronic Kidney Disease Epidemiology Collaboration equation. Nevertheless, the Cockcroft-Gault formula has been the mainstay in clinical pharmacology and medicine development for a long time, and it is the formula referenced in the vast majority of medicinal products’ SPCs in relation to dosing for renal function. These factors suggest an ongoing complexity in decision-making in terms of prescribing the regulatory recommended doses in clinical practice. Based on that, it would be interesting to examine whether and the extent to which patients treated with sitagliptin were more likely to be prescribed the SPC-specified dose with regard to the level of renal function after January 2018 (ie, when SPC renal thresholds changed to GFR). DPP-4 inhibitors are well tolerated, and renal function is the only criterion specified in SPCs to justify dose adjustment. Therefore, except for the difference between the renal threshold specification in CrCl in SPCs and estimated GFR use in the clinical practice, it is difficult to elucidate the reasons for patients being initiated at doses lower than SPC-specified. Interviews with health care professionals prescribing lower doses could be useful to understand the clinical rationale behind prescribing of lower than SPC-specified DPP-4 inhibitor doses. Evidence from dose-ranging studies showed that lower/lowest DPP-4 inhibitor doses were associated with smaller reductions in glycosylated hemoglobin.14, 15, 16, 17 Future observational studies are needed to confirm this effect in clinical practice.
Introduction The stroke-damaged brain area can be divided into the ischemic core and the penumbra around the ischemic core (Hossmann, 1994, Macdonald and Stoodley, 1998). The damage in the ischemic core occurs very quickly (within minutes to hours) and is mostly irreversible. The surrounding penumbra maintains residual blood flow and thus the neurons in this area can be potentially rescued by timely intervention (Ferrer and Planas, 2003, Liu et al., 2012) (Heiss, 2012). Different therapeutic strategies based on neuroprotection have been tried and shown to be efficacious in animal models. However, no neuroprotective strategy is yet available in human (Gladstone et al., 2002, Cheng et al., 2004, Endres et al., 2008). The reasons at the basis of the failure to translate efficacy from animal studies to the clinical setting might depend by different reasons ranging from differences in dosage, use of experimental models not mimicking the clinical setting (e.g. without typical comorbidities of stroke patients such as diabetes and hypertension) unfeasible routes of administration and timing of drug administration from the onset of stroke (Sena et al., 2007). Today, the researchers in the field are even reflecting whether the main focus of experimental and translational stroke research should shift from early neuroprotection to delayed mechanisms such as regeneration and plasticity (Roth and Liesz, 2016).