Clinical Effectiveness of Liraglutide Across Body Mass Index in Patients with Type 2 Diabetes in the United States: A Retrospective Cohort Study

Introduction

Clinical trials have shown that liraglutide effectively lowers glycated hemoglobin A1c (A1C) levels in adult patients with type 2 diabetes (T2D). However, no studies have evaluated the effectiveness of liraglutide by body mass index (BMI) in the United States (US) in clinical practice. This study examined liraglutide’s clinical effectiveness to lower A1C and body weight after 6 months in T2D patients stratified by baseline BMI.

Methods

This was a retrospective cohort study using the General Electric Centricity electronic medical records database. Adult patients with T2D (≥18 years and BMI≥ 25 kg/m²) and A1C >7% at baseline who started liraglutide between January 1, 2010 and January 31, 2013 and who did not use insulin or a glucagon-like peptide-1 analog 12 months before initiating liraglutide (N = 3,005) were selected. Changes from baseline, stratified by BMI, in A1C, body weight, A1C <7% goal attainment, and incidence of severe hypoglycemia at 6-month follow-up were examined.

Results

After 6 months, A1C levels decreased on average by 0.95%, 1.02%, 0.99%, and 0.84% for BMI categories 25.0–29.9 (n = 333), 30.0–34.9 (n = 793), 35.0–39.9 (n = 821), and ≥40.0 kg/m² (n = 1,058), respectively (P = 0.30). The proportions of patients achieving A1C <7% at 6 months were 38.2%, 37.0%, 40.9%, and 41.0% (P = 0.54). The absolute body weight decreased by 1.5 to 4.0 kg across BMI and the rate of severe hypoglycemia (0.2%) was low.

Conclusion

Patients with T2D experienced statistically significant decreases in A1C and body weight after initiating liraglutide regardless of their BMI. Liraglutide reduced A1C equally well across baseline BMI in clinical practice in the US.     

Feasibility of neuromuscular electrical stimulation in critically ill patients

Objective

Critically ill patients often develop intensive care unit–acquired weakness. Reduction in muscle mass and muscle strength occurs early after admission to the intensive care unit (ICU). Although early active muscle training could attenuate this intensive care unit–acquired weakness, in the early phase of critical illness, a large proportion of patients are unable to participate in any active mobilization. Neuromuscular electrical stimulation (NMES) could be an alternative strategy for muscle training. The aim of this study was to investigate the safety and feasibility of NMES in critically ill patients.

Design

This is an observational study.

Setting

The setting is in the medical and surgical ICUs of a tertiary referral university hospital.

Patients

Fifty patients with a prognosticated prolonged stay of at least 6 days were included on day 3 to 5 of their ICU stay. Patients with preexisting neuromuscular disorders and patients with musculoskeletal conditions limiting quadriceps contraction were excluded.

Intervention

Twenty-five minutes of simultaneous bilateral NMES of the quadriceps femoris muscle. This intervention was performed 5 days per week (Monday-Friday). Effective muscle stimulation was defined as a palpable and visible contraction (partial or full muscle bulk).

Measurements

The following parameters, potentially affecting contraction upon NMES, were assessed: functional status before admission to the ICU (Barthel index), type and severity of illness (Acute Physiology And Chronic Health Evaluation II score and sepsis), treatments possibly influencing the muscle contraction (corticosteroids, vasopressors, inotropes, aminoglycosides, and neuromuscular blocking agents), level of consciousness (Glasgow Coma Scale, score on 5 standardized questions evaluating awakening, and sedation agitation scale), characteristics of stimulation (intensity of the NMES, number of sessions per patient, and edema), and neuromuscular electrophysiologic characteristics. Changes in heart rate, blood pressure, oxygen saturation, respiratory rate, and skin reactions were registered to assess the safety of the technique.

Results

In 50% of the patients, an adequate quadriceps contraction was obtained in at least 75% of the NMES sessions. Univariate analysis showed that lower limb edema (P < .001), sepsis (P = .008), admission to the medical ICU (P = .041), and treatment with vasopressors (P = .011) were associated with impaired quadriceps contraction. A backward multivariate analysis identified presence of sepsis, lower limb edema, and use of vasopressors as independent predictors of impaired quadriceps contraction (R² = 59.5%). Patients responded better to NMES in the beginning of their ICU stay in comparison with after 1 week of ICU stay. There was no change in any of the safety end points with NMES.

Conclusions

Critically ill patients having sepsis, edema, or receiving vasopressors were less likely to respond to NMES with an adequate quadriceps contraction. Neuromuscular electrical stimulation is a safe intervention to be administered in the ICU.     

Pegylated asparaginase in combination with high-dose methotrexate for consolidation in adult acute lymphoblastic leukaemia in first remission: a pilot study

The German Multicentre acute lymphoblastic leukaemia (ALL) study group (GMALL) performed a pilot study using pegylated asparaginase (PEG-ASP) in combination with high-dose methotrexate as consolidation therapy in the 05/93 protocol. The aim of the study was an intra-individual comparison of two different doses of PEG-ASP in 26 patients, with regard to the depletion of asparagine in serum and toxicity. 'Pharmacokinetic' monitoring was performed to evaluate the effect of an intra-individual dose escalation of PEG-ASP from 500 to 1000 U/m2 intravenously in successive doses. Serum asparaginase activity was targeted at > or =100 U/l for 1 week and > or =50 U/l for 10 d. The second course of PEG-ASP was administered to 23 patients. Due to hypersensitivity reactions in five patients, only 18 patients were evaluable for pharmacokinetic monitoring. With respect to the PEG-ASP activity, an effective depletion of asparagine could be postulated in the majority of patients during 10 d after the first administration. The effect of an intraindividual dose escalation form 500 to 1000 U/m2 was evaluable in 17 of 22 patients. An increment in peak PEG-ASP activity >70% was observed in 65% of the patients. PEG-ASP was well tolerated. Despite the long half-life of PEG-ASP, neither pancreatic nor central nervous toxicities occurred among the 26 adult patients treated in this pilot study.     

Recent developments in noradrenergic neurotransmission and its relevance to the mechanism of action of certain antihypertensive agents

This report reviews a number of significant developments in the fields of noradrenergic transmission and adrenergic receptors which suggest that, in addition to the classical postsynaptic adrenoceptors, there are also presynaptic adrenoceptors that help modulate the release of norepinephrine (NE) from peripheral as well as central noradrenergic nerve endings during nerve stimulation. In particular, stimulation of presynaptic alpha-adrenoceptors reduces this release of transmitter and the reverse is observed after blockade of these receptors. Clearcut pharmacological differences exist between the postsynaptic alpha 1-adrenoceptors that mediate the responses of certain organs and the presynaptic alpha 2-adrenoceptors that modulate the NE release during nerve stimulation. Therefore, subclassification of alpha-adrenoceptors into alpha 1 and alpha 2 subtypes is warranted but must be considered to be independent of the anatomical location of these receptors. Some noradrenergic nerve endings have also been shown to possess beta-adrenergic receptors, the stimulation of which increases the quantity of transmitter released by nerve impulses. Physiologically, these receptors could be activated by circulating epinephrine (E) and be involved in essential hypertension. A third type of catecholamine receptor found at the noradrenergic nerve ending is the inhibitory dopamine (DA) receptor, which might be of significance in the development of new antihypertensive agents. Application of these new concepts of noradrenergic neurotransmission and the subclassification of alpha-adrenoceptors to the treatment of hypertension is presented. Clonidine, for example, appears to be a potent alpha 2-adrenoceptor agonist; the central receptor involved in its antihypertensive action is pharmacologically an alpha 2-type but located postsynaptically. Clonidine also induces activation of peripheral presynaptic alpha 2-adrenoceptors, which might contribute to its cardiovascular action. The antihypertensive effects of alpha-methyldopa are related to the formation of alpha-methylnorepinephrine, a preferential alpha 2-adrenoceptor agonist, which can stimulate peripheral presynaptic alpha 2-adrenoceptors leading to a decrease of NE release and a reduction in sympathetic tone. Prazosin is a new antihypertensive agent the mechanism of action of which involves a selective blockade of postsynaptic alpha 1-adrenoceptors. This drug does not antagonize several effects of clonidine that are mediated via alpha 2-adrenoceptors. The mechanisms presently considered to account for the antihypertensive activity of beta-adrenoceptor blocking agents are numerous. It is proposed that blockade of peripheral presynaptic facilitatory beta-adrenoceptors could be of significance in the antihypertensive action of these drugs.     

Prandial insulin substitution with insulin lispro or insulin lispro mid mixture vs. basal therapy with insulin glargine: a randomized controlled trial in patients with type 2 diabetes beginning insulin therapy

PURPOSE: To compare the effects of prandial insulin therapy focusing on postprandial glucose control vs. basal insulin therapy focusing on fasting glucose control in patients with type 2 diabetes. METHODS: This was an open-label, randomized, parallel, three-arm multicenter trial in patients with type 2 diabetes starting insulin treatment. Patients (n=159) were randomly assigned to 24-week treatment with 3x daily insulin lispro, 3x daily lispro mid mixture (MidMix; 50% lispro, 50% protaminated lispro), or 1x daily insulin glargine; oral antihyperglycemic agents were discontinued. Primary end point was the postprandial glucose excursion 2 h after breakfast at the end of study. Secondary outcomes included HbA1c, self-monitored blood glucose profiles, hypoglycemic episodes, body weight, and patient satisfaction. RESULTS: At the end of study, glucose excursions 2 h after breakfast were significantly lower with lispro and MidMix than with glargine (P<.001 for each vs. glargine): lispro, -0.6+/-2.0 mmol/l; MidMix, +0.8+/-2.4 mmol/l; glargine, +2.5+/-2.4 mmol/l. Fasting glucose decreases were significantly greater with glargine (-2.6+/-2.4 mmol/l) than with lispro or MidMix (-0.9+/-2.2 mmol/l; +0.9+/-1.8 mmol/l). Nevertheless, HbA1c decreased by 1.1% (lispro) and 1.2% (MidMix), vs. 0.3% with glargine. Hypoglycemic episodes were rare with 1-1.5 self-reported episodes per 100 patient-days. CONCLUSIONS: In patients with type 2 diabetes starting insulin, 3x daily prandial treatment with a rapid-acting analog focusing on postprandial glucose values enabled better control of postprandial and circadian blood glucose profiles than once-daily glargine, in spite suboptimal fasting glucose levels, which targets fasting glucose values. These results support studies suggesting that control of postprandial hyperglycemia plays a key role in achieving HbA1c targets.