Managing pasireotide-associated hyperglycemia: a randomized,open-label,Phase IV study

Purpose

Pasireotide is an effective treatment for acromegaly and Cushing’s disease, although treatment-emergent hyperglycemia can occur. The objective of this study was to assess incretin-based therapy versus insulin for managing pasireotide-associated hyperglycemia uncontrolled by metformin/other permitted oral antidiabetic drugs.

Methods

Multicenter, randomized, open-label, Phase IV study comprising a core phase (≤?16-week pre-randomization period followed by 16-week randomized treatment period) and optional extension (ClinicalTrials.gov ID: NCT02060383). Adults with acromegaly (n?=?190) or Cushing’s disease (n?=?59) received long-acting (starting 40 mg IM/28 days) or subcutaneous pasireotide (starting 600 µg bid), respectively. Patients with increased fasting plasma glucose (≥?126 mg/dL on three consecutive days) during the 16-week pre-randomization period despite metformin/other oral antidiabetic drugs were randomized 1:1 to open-label incretin-based therapy (sitagliptin followed by liraglutide) or insulin for another 16 weeks. The primary objective was to evaluate the difference in mean change in HbA_1c from randomization to end of core phase between incretin-based therapy and insulin treatment arms.

Results

Eighty-one (32.5%) patients were randomized to incretin-based therapy (n?=?38 received sitagliptin, n?=?28 subsequently switched to liraglutide; n?=?12 received insulin as rescue therapy) or insulin (n?=?43). Adjusted mean change in HbA_1c between treatment arms was – 0.28% (95% CI – 0.63, 0.08) in favor of incretin-based therapy. The most common AE other than hyperglycemia was diarrhea (incretin-based therapy, 28.9%; insulin, 30.2%). Forty-six (18.5%) patients were managed on metformin (n?=?43)/other OAD (n?=?3), 103 (41.4%) patients did not require any oral antidiabetic drugs and 19 patients (7.6%) were receiving insulin at baseline and were not randomized.

Conclusion

Many patients receiving pasireotide do not develop hyperglycemia requiring oral antidiabetic drugs. Metformin is an effective initial treatment, followed by incretin-based therapy if needed.

ClinicalTrials.gov ID: NCT02060383.

     

Long-term reproducibility of routine ambulatory blood pressure monitoring in stable pediatric renal transplant recipients

BACKGROUND: The aim of this study was to evaluate, in stable pediatric renal transplant recipients, the long-term reproducibility of average office and ambulatory blood pressure (BP) readings and day-to-night BP variability under similar clinical conditions. METHODS: The study involved 18 pediatric kidney transplant recipients who had repeated routine office and 24-h ambulatory BP monitoring (ABPM) in three visits, 12 months apart, over a 2-year period. Reproducibility of office and ambulatory BP averages between pairwise measurements were analyzed by calculating the mean difference and the standard deviation of the difference (SDD). Nondippers were arbitrarily defined by applying both a pediatric and an adult definition, respectively. RESULTS: Throughout the 2-year period, there were no significant differences in mean office, 24-h, daytime, night-time systolic, and diastolic BP values. Overall, SDD were lower for ambulatory BP recordings than for office BP measurements indicating a better long-term reproducibility for ABPM compared with office BP readings. The SDD for systolic and diastolic BP ranged from 12.4 to 13.7 and 6.3 to 9.5 for office BP and from 6.2 to 7.3 and 5.1 to 5.6 for 24-h BP, respectively. Regardless of the definition applied to define dipper and nondipper status, only half of the study group showed consistency in their circadian BP variability when comparing the three ABPMs. CONCLUSIONS: The present study demonstrates that long-term reproducibility of ABPM is superior to that for office measurements. Day-to-night BP variability, however, appears to change over time, making it questionable to classify a recipient as a dipper or nondipper during a single ABPM recording.     

Circulating leptin and thyroid dysfunction

The identification and sequencing of the ob gene and its product, leptin, in 1994 opened new insights in the study of the mechanisms controlling body weight and led to a surge of research activity. Since its discovery, leptin has been the subject of an enormous amount of work especially within the fields of nutrition, metabolism and endocrinology. Leptin is accepted as an adipose signal, and even though the underlying mechanisms are not fully clarified, leptin, in addition to the thyroid hormones, is believed to be involved in regulation during the switch from the fed to the starved state. It is not clear whether leptin and the melanocortin pathways interact with the thyroid axis under physiological conditions other than during starvation or in response to severe illness, both states in which the hypothalamo-pituitary-thyroid axis may be severely suppressed. In addition to the suggested central relationship between leptin and thyroid hormones, there might also be a peripheral relationship although this effect is not clear. Both thyroid hormones and leptin might be involved in the adaptive thermogenesis through mitochondrial uncoupling proteins and heat production because both thyroxine and triiodothyronine are involved in the starvation-induced decrease in thermogenesis. Both rodent and human studies of leptin have failed to show any consistent relationship between thyroid function and serum leptin concentrations. However, leptin might have an important role in thyroid pathophysiology due to thyroid hormone involvement in thermogenesis and regulation of uncoupling proteins. In this review, we have focused on leptin in relation to thyroid pathophysiology.     

Improved Hand Function,Self‐Rated Health,and Decreased Activity Limitations: Results After a Two‐Month Hand Osteoarthritis Group Intervention

Objective

To evaluate the effects on hand function, activity limitations, and self‐rated health of a primary care hand osteoarthritis (OA) group intervention. Hand OA causes pain, impaired mobility, and reduced grip force, which cause activity limitations. OA group interventions in primary care settings are sparsely reported.

Methods

Sixty‐four individuals with hand OA agreed to participate; 15 were excluded due to not fulfilling the inclusion criteria. The 49 remaining (90% female) participated in an OA group intervention at a primary care unit with education, paraffin wax bath, and hand exercise over a 6‐week period. Data were collected at baseline, end of intervention, and after 1 year. Instruments used were the Grip Ability Test (GAT), the Signals of Functional Impairment (SOFI), dynamometry (grip force), hand pain at rest using a visual analog scale (VAS), the Patient‐Specific Functional Scale (PSFS), the Quick Disabilities of the Arm, Shoulder, and Hand (Quick‐DASH), and the EuroQol VAS (EQ VAS). Data were analyzed using nonparametric statistics.

Results

Hand function, activity limitation, and self‐rated health significantly improved from baseline to end of intervention, grip force (right hand: P < 0.001; left hand: P = 0.008), SOFI (P = 0.011), GAT (P < 0.001), hand pain at rest (P < 0.001), PSFS (1: P = 0.008, 2: P < 0.001, and 3: P = 0.004), Quick‐DASH (P = 0.001), and EQ VAS (P = 0.039), and the effects were sustained after 1 year.

Conclusion

The hand OA group intervention in primary care improves hand function, activity limitation, and self‐rated health. The benefits are sustained 1 year after completion of the intervention.

     

Molecular characterization of chromosome 7 long arm deletions in myeloid disorders

Partial deletion of the long arm of chromosome 7 is a common abnormality in the bone marrow cells of patients with myelodysplastic syndrome (MDS) or acute nonlymphocytic leukemia (ANLL). This study was undertaken to characterize the chromosome breakpoints in molecular terms and to determine if hemizygosity or submicroscopic deletions occur in patients without any cytogenetically detectable abnormality of chromosome 7. We studied restriction fragment length polymorphisms with 10 chromosome 7-specific DNA probes in separated WBC fractions. No molecular abnormalities occurred in lymphocyte-derived DNA. Several probes located in band 7q22 or distally thereof detected deletion of one allele in granulocyte-derived DNA from all four patients with chromosome 7 long arm deletion. In the granulocytes of one patient heterozygosity for the T cell receptor beta chain gene (in band 7q35) indicated that the deletion was interstitial. NJ-3, a proalpha2(I)collagen gene probe (in band 7q21-22) detected heterozygosity in the granulocytes of one patient. No hemizygosity or deletions were found in four patients with two normal chromosomes 7. These results confirm that mature granulocytes but not lymphocytes are derived from the abnormal clone. Interstitial deletions exist, and the extent of deleted genomic material varies among patients.     

Intravenous Immunoglobulin and Rituximab for Cerebellar Ataxia with Glutamic Acid Decarboxylase Autoantibodies

Cerebellar ataxia associated with glutamic acid decarboxylase autoantibodies (GAD-ab) is a rare and usually slow progressive disease with moderate to severe gait and limb ataxia, dysarthria, and nystagmus. The treatment for this condition is still being discussed. We report the cases of three patients with GAD-ab cerebellar ataxia treated successively with intravenous immunoglobulin (IVIg) and rituximab. Symptoms improved in one case after rituximab therapy and were stabilized in another after a combined therapy of IVIg and rituximab. The third patient continued to worsen despite these treatments. We conclude that IVIg and rituximab therapy could improve or stabilize GAD-ab cerebellar ataxia. Early treatment, the lack of cerebellar atrophy on magnetic resonance imaging, and a subacute onset of the symptoms could be decisive prognostic factors.     

Hemodynamic causes of exercise intolerance in Fontan patients

Background

Exercise intolerance is frequent among Fontan patients and an important determinant for quality of life. This study investigated the hemodynamic causes of impaired exercise capacity in Fontan patients with particular focus on the influence of stroke volume index (SVI) and heart rate (HR).

Methods and results

In 38 Fontan patients, peak oxygen consumption (VO₂), SVI and HR were recorded during incremental load exercise test and compared with 19 age and gender matched controls.SVI (ml/m²) was lower in patients than controls during warm-up (28[26–31] vs. 35[30–39], p = 0.0093), at submaximal (40[37–43] vs. 55[51–59], p < 0.0001) and at maximal exercise (38[35–40] vs. 54[51–58], p < 0.0001). Similarly, HR (% of expected maximum) was lower in patients at warm-up (45[43–48]% vs. 64[57–64]%, p < 0.0001), submaximal (71[68–75]% vs 85[82–88]%, p < 0.0001) and maximal exercise (84[80–88]% vs. 97[95–99]%, p < 0.0001). Furthermore, SVI dropped 14% (from 44[41–48] to 38[35–40] ml/m²) in Fontan patients from the peak plateau to maximal exercise vs. 5% (from 57[53–61] to 54[51–58] ml/m²) in controls, p < 0.0001. The low SVI and HR explained 67% and 20% of the difference in peak VO₂ between Fontan patients and controls respectively.

Conclusion

SVI decreased significantly in Fontan patients near the end of maximal effort exercise. The low SVI at maximal exercise was the most important hemodynamic factor limiting exercise capacity in Fontan patients, whereas chronotropic impairment had a smaller impact. The low SVI and HR at maximal exercise accounted for the difference in peak VO₂ between Fontan patients and controls in this study.

Clinical trial registration

http://www.cvk.sum.dk/CVK/Home/English.aspx (protocol nr: H-3-2010-045).