Immunogenicity, efficacy, and safety of biosimilar insulin glargine (Gan & Lee glargine) compared with originator insulin glargine (Lantus®) in patients with type 2 diabetes after 26 weeks' treatment: A randomized open label study.

AIM: To evaluate the equivalence of immunogenicity, safety and efficacy of Gan & Lee (GL) Glargine (Basalin®; Gan & Lee Pharmaceutical) with that of the reference product (Lantus®) in adult participants with type 2 diabetes mellitus. METHODS: This was a phase 3, multicenter, open-label, equivalence trial conducted across 57 sites. In total, 567 participants with type 2 diabetes mellitus were randomized in a 1:1 ratio to undergo treatment with either GL Glargine or Lantus® for 26 weeks. The primary endpoint was the proportion of participants in each treatment arm who manifested treatment-induced anti-insulin antibodies (AIA). Secondary endpoints included efficacy and safety metrics, changes in glycated haemoglobin levels, and a comparative assessment of adverse events. Results were analysed using an equivalence test comparing the limits of the 90% confidence interval (CI) for treatment-induced AIA development to the prespecified margins. RESULTS: The percentages of participants positive for treatment-induced glycated haemoglobin by week 26 were similar between the GL Glargine (19.2%) and Lantus® (21.3%) treatment groups, with a treatment difference of -2.1 percentage points and a 90% CI (-7.6%, 3.5%) (predefined similarity margins: -10.7%, 10.7%). The difference in glycated haemoglobin was -0.08% (90% CI, -0.23, 0.06). The overall percentage of participants with any treatment-emergent adverse events was similar between the GL Glargine (80.1%) and Lantus® (81.6%) treatment groups. CONCLUSIONS: GL Glargine was similar to Lantus® in terms of immunogenicity, efficacy, and safety, based on the current study.

Voice abnormality in adults with congenital and adult-acquired growth hormone deficiency.

CONTEXT: Adult males with congenital, untreated, severe GH deficiency (GHD) due to genetic GHRH receptor deficiency exhibit distinctive, high-pitched, and raspy voice characteristics. OBJECTIVE/DESIGN: To determine the physical underpinning of this phenomenon, we performed voice recordings, translarynx impedance measurements, spectral analysis, and estimates of spectral complexity [approximate entropy (ApEn)] in four affected men. Results were compared with those obtained in four men with untreated adult-onset GHD and a normal male population. RESULTS: Congenital GHD subjects had a high-pitched voice with a fundamental frequency typical of normal females (174-266 Hz). Their frequency spectra were characterized by abnormal harmonics, with reversal/interruption of the normal amplitude decay among higher-order harmonics, findings consistent with a creaky quality of the voice. Patients with adult-onset GHD, acquired at ages 31, 38, and 40 yr, had a normal male pitch (fundamental frequency, 117-154 Hz) but pathologically low ApEn values, corresponding to a breathy quality of the voice and suggesting abnormal vocal fold function. A fourth patient who acquired GHD at age 22 yr had a pitch intermediate between male and female, high ApEn, and a spectral pattern similar to the congenital GHD patients. CONCLUSIONS: This study demonstrates an effect of GH on laryngeal size and vocal fold compliance that results in a high pitch and disordered spectral quality. The time of onset of GHD determines which type of abnormality predominates.

The Impact of congenital, severe, untreated growth hormone (GH) deficiency on bone size and density in young adults: insights from genetic GH-releasing hormone receptor deficiency.

GH and IGF-I have well recognized effects on bone elongation during development, but their importance for bone mineralization and structure during the growth phase are less well understood. Because children with GH deficiency are generally treated with GH, little detailed information exists in humans about the effects of long-term GH deficiency on bone development. The recently described syndrome of genetic GHRH receptor deficiency in Pakistan (dwarfism of Sindh) affords a unique opportunity to examine the question of GH deficiency on bone development because the affected patients have congenital, severe, isolated GH deficiency, which had never been treated because of societal reasons. We performed dual energy x-ray absorptiometry scans in four adult males (age, 23-30 yr) to address the question of bone mineralization. Areal bone mineral density (BMD) was low (mean Z scores: -3.3, -2.1, -3.7, and -1.7) in the lumbar spine, femoral neck, forearm, and total skeleton, respectively. This low areal BMD is in part caused by the small bone size in these dwarfed patients. When corrected for size, volumetric BMD (bone mineral apparent density) was normal to near normal (mean Z scores: -1.2, +0.8, and +0.8 for lumbar spine, femoral neck and total skeleton, respectively). We conclude that GH/IGF-I deficiency has relatively little impact on bone mineralization during the bone accretion phase. This is in marked contrast to their effect on bone elongation and overall bone size.

Haplotype analysis of the growth hormone releasing hormone receptor locus in three apparently unrelated kindreds from the indian subcontinent with the identical mutation in the GHRH receptor.

The growth hormone releasing hormone receptor (GHRHR) plays a critical role in growth. We identified three nominally unrelated kindreds harboring the identical mutation (E72X) in GHRHR, the gene that encodes GHRHR; all three families originated in the Indian subcontinent. Because of the relative geographic proximity of these populations, we employed haplotype analysis in the region of GHRHR to determine the likelihood that this mutation occurred in a common ancestor rather than having occurred on separate occasions in different individuals. Members of all three kindreds segregating the E72X mutation were genotyped for highly polymorphic dinucleotide repeat microsatellites in a 15.5 centimorgan (cM) region around GHRHR on chromosome 7p15. We conclude that the affected individuals share a common ancestor, and we use the association with linked markers to estimate the age of this unique mutation.

Apolipoprotein E gene polymorphism alters lipids before pancreas transplantation.

BACKGROUND: Pancreas transplantation (PTX) improves lipids in patients with type 1 diabetes mellitus. However, there are patients who have persistent abnormal lipids or develop new hyperlipidemia despite PTX. One factor that may influence the lipid profile is apolipoprotein E (Apo E) genotype. Apo E polymorphism, particularly E2 and E4 alleles, increases the risk of dyslipidemia. Apo E2 has also been found to increase risk of diabetic nephropathy and so may be more prevalent in PTX candidates. METHODS: This study evaluated fasting-lipid profiles in type 1 diabetes patients who were pancreas transplant candidates to prospectively evaluate the impact of Apo E genotype on dyslipidemia before and after PTX. RESULTS: Presence of one or more E4 alleles resulted in higher triglycerides ( =0.0446), lower HDL ( =0.0247), and a higher cholesterol-to-HDL (C/H) ratio ( =0.0405) before PTX when compared with those with E3/3 genotype. After PTX, lipids improved so there was no longer a difference in fasting lipids between patients with an E4 allele and E3/3 genotype. Presence of an E2 allele had no significant impact on fasting lipids before or after PTX. CONCLUSIONS: Presence of an Apo E4 allele worsened HDL, triglycerides, and C/H ratio before PTX compared with those with E3/3 genotype, whereas the presence of an Apo E2 allele had no significant effect on lipids before or after PTX. Thus, Apo E4 has a larger impact than Apo E2 on fasting-lipid profile in PTX candidates, and Apo E gene polymorphism does not worsen lipid dyslipidemia after PTX, despite introduction of immunosuppressant medications known to cause dyslipidemia.

Pulsatile growth hormone secretion persists in genetic growth hormone-releasing hormone resistance.

Growth hormone (GH) secretion is regulated by GH-releasing hormone (GHRH), somatostatin, and possibly ghrelin, but uncertainty remains about the relative contributions of these hypophysiotropic factors to GH pulsatility. Patients with genetic GHRH receptor (GHRH-R) deficiency present an opportunity to examine GH secretory dynamics in the selective absence of GHRH input. We studied circadian GH profiles in four young men homozygous for a null mutation in the GHRH-R gene by use of an ultrasensitive GH assay. Residual GH secretion was pulsatile, with normal pulse frequency, but severely reduced amplitude (<1% normal) and greater than normal process disorder (as assessed by approximate entropy). Nocturnal GH secretion, both basal and pulsatile, was enhanced compared with daytime. We conclude that rhythmic GH secretion persists in an amplitude-miniaturized version in the absence of a GHRH-R signal. The nocturnal enhancement of GH secretion is likely mediated by decreased somatostatin tone. Pulsatility of residual GH secretion may be caused by oscillations in somatostatin and/or ghrelin; it may also reflect intrinsic oscillations in somatotropes.