Pharmacokinetic and Pharmacodynamic Responses of Insulin Degludec in African American,White, and Hispanic/Latino Patients With Type 2 Diabetes Mellitus

Background

Pharmacokinetic and pharmacodynamic profiles of exogenous insulin may be affected by intrinsic factors, such as age, ethnicity/race, and hepatic and renal function. Insulin degludec (IDeg) is a basal insulin with an ultralong duration of action and a flat and stable glucose-lowering effect profile.

Objective

The purpose of this study was to investigate whether the pharmacokinetic and pharmacodynamic responses to IDeg at steady state vary according to patient race/ethnicity.

Methods

This randomized, single-center, double-blind, 2-period crossover trial investigated responses to IDeg in 59 patients with type 2 diabetes mellitus from 3 groups: African American, Hispanic/Latino, and white. Patients were allocated randomly to a sequence of 2 treatment periods, separated by a 7- to 21-day washout period, with once-daily IDeg or insulin detemir dosing for 6 days at a predefined fixed dose level (0.6 U/kg). Differences in pharmacokinetic and pharmacodynamic variables among groups were analyzed using an ANOVA with treatment period, an interaction between race/ethnicity, and treatment as fixed factors, subject as a random effect, and residual variance, depending on treatment.

Results

Total exposure to IDeg during one dosing interval at steady state (AUC_IDeg,τ,SS) was similar among the racial/ethnic groups (ratio [95% CI]: African American vs white, 1.10 [0.91–1.31]; African American vs Hispanic/Latino, 1.13 [0.95–1.34]; and Hispanic/Latino vs white, 0.97 [0.82–1.16]). The total glucose-lowering effect of IDeg (AUC_GIR,τ,SS) was also similar among the groups, with no statistically significant difference in pairwise comparisons (1940, 1735, and 2286 mg/kg in African American, white, and Hispanic/Latino patients, respectively). Steady state was reached in all groups after 2 to 3 days of dosing. In all groups, both exposure and glucose-lowering effect for IDeg were evenly distributed between the first and second 12 hours of the 24-hour dosing interval at steady state (mean AUC_{IDeg,0–12h,SS}/AUC_IDeg,τ,SS = 53%–54%; AUC_{GIR,0-–12h,SS}/AUC_GIR,τ,SS = 47%–52%).

Conclusion

The similar pharmacokinetic and pharmacodynamic responses to IDeg in 3 racial/ethnic groups of patients with type 2 diabetes mellitus suggest that the flat, stable, and ultralong pharmacokinetic and pharmacodynamic profiles of IDeg are preserved irrespective of race/ethnicity. Although insulin doses must be adjusted on an individual basis, similar pharmacokinetic and pharmacodynamic responses to IDeg are observed in patients with differing race/ethnicity.     

Risk factors for more severe regional musculoskeletal symptoms: a two-year prospective study of a general working population

OBJECTIVE: To quantify the relative contribution of work-related physical and psychosocial factors, individual factors, and health-related factors to the development of more severe musculoskeletal pain in the neck and upper limbs and the back and lower limbs. METHODS: In this cohort study of 5,604 workers from industrial and service companies, we collected information on work-related physical and psychosocial exposures and on individual and health-related factors. Questionnaires were completed at baseline by 4,006 participants (71.5%) and after 24 months by 3,276 (82%). At followup, participants with no or minor pain were included in Cox regression analyses to determine which factors predicted more severe regional pain. RESULTS: Of the 4,006 baseline respondents, only 7.7% were free of regional pain. A total of 1,513 participants were free of severe pain at baseline and completed the 24-month followup. Highly repetitive work predicted arm pain, heavy lifting and prolonged standing predicted low back pain, and heavy pushing or pulling predicted lower limb pain. Low job satisfaction predicted neck/shoulder pain and lower limb pain, whereas other psychosocial work place factors were only of marginal importance. High levels of fear avoidance were associated with arm pain and lower limb pain. A high body mass index was highly associated with lower limb pain. CONCLUSION: Very few workers are totally free of pain in musculoskeletal regions, and we question the concept of incidence of musculoskeletal pain. The transition from no or minor pain to more severe pain was influenced by physical and psychosocial work place factors together with individual and health-related factors.     

Similar risk of exercise‐related hypoglycaemia for insulin degludec to that for insulin glargine in patients with type 1 diabetes: a randomized cross‐over trial

We compared changes in blood glucose (BG) and risk of hypoglycaemia during and after exercise in 40 patients with type 1 diabetes (T1D) treated with insulin degludec (IDeg) or insulin glargine (IGlar) in a randomized, open‐label, two‐period, crossover trial. After individual titration and a steady‐state period, patients performed 30 min of moderate‐intensity cycle ergometer exercise (65% peak rate of oxygen uptake). BG, counter‐regulatory hormones and hypoglycaemic episodes were measured frequently during and for 24 h after exercise. BG changes during exercise were similar with IDeg and IGlar [estimated treatment difference (ETD) for maximum BG decrease: 0.14 mmol/l; 95% confidence interval (CI) ?0.15, 0.42; p = 0.34], as was mean BG (ETD ?0.16 mmol/l; 95% CI ?0.36, 0.05; p = 0.13). No hypoglycaemic episodes occurred during exercise. Post‐exercise mean BG, counter‐regulatory hormone response and number of hypoglycaemic episodes in 24 h after starting exercise were similar with IDeg (18 events in 13 patients) and IGlar (23 events in 15 patients). This clinical trial showed that, in patients with T1D treated with a basal‐bolus regimen, the risk of hypoglycaemia induced by moderate‐intensity exercise was low with IDeg and similar to that with IGlar.     

The prognostic value of the Tpeak-Tend interval in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction

Introduction

The Tpeak-Tend interval (TpTe) has been linked to increased arrhythmic risk. TpTe was investigated before and after primary percutaneous coronary intervention (pPCI) in patients with ST-segment elevation myocardial infarction (STEMI).

Method

Patients with first-time STEMI treated with pPCI were included (n = 101; mean age 62 years; range 39-89 years; 74% men). Digital electrocardiograms were taken pre- and post-PCI, respectively. Tpeak-Tend interval was measured in leads with limited ST-segment deviation. The primary end point was all-cause mortality during 22 ± 7 months (mean ± SD) of follow-up.

Results

Pre- and post-PCI TpTe were 104 milliseconds [98-109 milliseconds] and 106 milliseconds [99-112 milliseconds], respectively (mean [95% confidence interval], P = .59). A prolonged pre-PCI TpTe was associated with increased mortality (hazard ratio, 10.5 [1.7-20.4] for a cutoff value of 100 milliseconds). Uncorrected QT and heart rate-corrected QT intervals (Fridericia-corrected QT) were prolonged after PCI (QT: 401 vs 410 milliseconds, P = .022, and Fridericia-corrected QT: 430 vs 448 milliseconds, P < .0001).

Conclusion

In patients with STEMI undergoing pPCI, pre-PCI TpTe predicted subsequent all-cause mortality, and the QT interval was increased after the procedure.