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The Journal of Clinical Endocrinology... Jun 2023Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region,... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if not controlled.
OBJECTIVE
The primary end point was change from baseline in hyperphagia using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Other end points included Global Impression Scores, and changes in body composition, behaviors, and hormones.
METHODS
In DESTINY PWS, a 13-week, randomized, double-blind, placebo-controlled, phase 3 trial, 127 participants with PWS aged 4 years and older with hyperphagia were randomly assigned 2:1 to diazoxide choline extended-release tablet (DCCR) or placebo.
RESULTS
DCCR did not significantly improve hyperphagia (HQ-CT least-square mean (LSmean) [SE] -5.94 [0.879] vs -4.27 [1.145]; P = .198), but did so in participants with severe hyperphagia (LSmean [SE] -9.67 [1.429] vs -4.26 [1.896]; P = .012). Two of 3 secondary end points were improved (Clinical Global Impression of Improvement [CGI-I]; P = .029; fat mass; P = .023). In an analysis of results generated pre-COVID, the primary (HQ-CT; P = .037) and secondary end points were all improved (CGI-I; P = .015; Caregiver Global Impression of Change; P = .031; fat mass; P = .003). In general, DCCR was well tolerated with 83.3% in the DCCR group experiencing a treatment-emergent adverse event and 73.8% in the placebo group (not significant).
CONCLUSION
DCCR did not significantly improve hyperphagia in the primary analysis but did in participants with severe baseline hyperphagia and in the pre-COVID analysis. DCCR treatment was associated with significant improvements in body composition and clinician-reported outcomes.
Topics: Humans; Prader-Willi Syndrome; Diazoxide; COVID-19; Obesity; Hyperphagia
PubMed: 36639249
DOI: 10.1210/clinem/dgad014 -
Hormone Research in Paediatrics 2022Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in neonates, infants, and children. Since the first case descriptions in the 1950s, the... (Review)
Review
Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in neonates, infants, and children. Since the first case descriptions in the 1950s, the field has advanced significantly. It was the development of the insulin radioimmunoassay by Yalow and Berson a decade later that made it possible to demonstrate that this form of persistent hypoglycemia was caused by insulin, and a few years later, Drash described the successful treatment of children with hyperinsulinism with the antihypertensive diazoxide, which until today remains the only approved treatment for hyperinsulinism. In the mid 1970s, Baker and Stanley described that hyperinsulinism can be recognized by inappropriate responses of metabolic fuels and hormones during the course of a provocative fasting challenge. Later, advances in molecular genetics led to the discovery of the different genetic subtypes of hyperinsulinism. One of the most impactful discoveries in the field was the recognition of the focal form of hyperinsulinism and the development of 18F-DOPA PET for the localization of focal lesions before surgery which has resulted in the possibility of cure for children with focal disease. However, treatment options for children with nonfocal diazoxide-unresponsive hyperinsulinism have continued to be limited. New drug development programs for hyperinsulinism promise to change this in the next few years. Unfortunately, despite all these advances, children with hyperinsulinism around the world continue to experience neurological sequelae at high rates, highlighting the importance of early diagnosis and effective treatment.
Topics: Child; Humans; Infant; Infant, Newborn; Antihypertensive Agents; Congenital Hyperinsulinism; Diazoxide; Insulin
PubMed: 36446321
DOI: 10.1159/000526442 -
PloS One 2021Diazoxide is the first-line drug for treating hyperinsulinism and the only pharmacological agent approved for hyperinsulinism by the Federal Drug Administration. This... (Meta-Analysis)
Meta-Analysis
Diazoxide is the first-line drug for treating hyperinsulinism and the only pharmacological agent approved for hyperinsulinism by the Federal Drug Administration. This systemic review and meta-analysis aimed to investigate the efficacy and safety of diazoxide for treating hyperinsulinemic hypoglycemia (HH). The meta-analysis of the efficacy and safety of diazoxide in treating HH was performed by searching relevant studies in the PubMed, Embase, and Cochrane databases. The findings were summarized, and the pooled effect size and its 95% confidence interval (CI) were calculated. A total of 6 cohort studies, involving 1142 participants, met the inclusion criteria. Among the cohort studies, the pooled estimate of the response rate of diazoxide therapy was 71% (95% CI 50%-93%, Pheterogeneity< 0.001, I2 = 98.3%, Peffect< 0.001). The common side effects were hypertrichosis (45%), fluid retention (20%), gastrointestinal reaction (13%), edema (11%), and neutropenia (9%). Other adverse events included pulmonary hypertension (2%) and thrombocytopenia (2%). This meta-analysis suggested that diazoxide was potentially useful in HH management; however, it had some side effects, which needed careful monitoring. Furthermore, well-designed large-scale studies, such as randomized controlled trials, might be necessary in the future to obtain more evidence.
Topics: Antihypertensive Agents; Diazoxide; Humans; Hyperinsulinism; Hypertrichosis; Hypoglycemia; Treatment Outcome; Vasodilator Agents
PubMed: 33571197
DOI: 10.1371/journal.pone.0246463 -
British Medical Journal Nov 1972
Topics: Adenoma, Islet Cell; Adult; Catecholamines; Cyclic AMP; Diazoxide; Glucose; Glycogen Storage Disease; Humans; Hypoglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Liver; Secretory Rate
PubMed: 4344353
DOI: No ID Found -
Diabetic Medicine : a Journal of the... Jan 2019Congenital hyperinsulinism is a rare disease, but is the most frequent cause of persistent and severe hypoglycaemia in early childhood. Hypoglycaemia caused by excessive... (Review)
Review
Congenital hyperinsulinism is a rare disease, but is the most frequent cause of persistent and severe hypoglycaemia in early childhood. Hypoglycaemia caused by excessive and dysregulated insulin secretion (hyperinsulinism) from disordered pancreatic β cells can often lead to irreversible brain damage with lifelong neurodisability. Although congenital hyperinsulinism has a genetic cause in a significant proportion (40%) of children, often being the result of mutations in the genes encoding the K channel (ABCC8 and KCNJ11), not all children have severe and persistent forms of the disease. In approximately half of those without a genetic mutation, hyperinsulinism may resolve, although timescales are unpredictable. From a histopathology perspective, congenital hyperinsulinism is broadly grouped into diffuse and focal forms, with surgical lesionectomy being the preferred choice of treatment in the latter. In contrast, in diffuse congenital hyperinsulinism, medical treatment is the best option if conservative management is safe and effective. In such cases, children receiving treatment with drugs, such as diazoxide and octreotide, should be monitored for side effects and for signs of reduction in disease severity. If hypoglycaemia is not safely managed by medical therapy, subtotal pancreatectomy may be required; however, persistent hypoglycaemia may continue after surgery and diabetes is an inevitable consequence in later life. It is important to recognize the negative cognitive impact of early-life hypoglycaemia which affects half of all children with congenital hyperinsulinism. Treatment options should be individualized to the child/young person with congenital hyperinsulinism, with full discussion regarding efficacy, side effects, outcomes and later life impact.
Topics: Antihypertensive Agents; Congenital Hyperinsulinism; Diazoxide; Gastrointestinal Agents; Glucagon; Humans; Hypoglycemia; Pancreatectomy; Potassium Channels, Inwardly Rectifying; Precision Medicine; Sulfonylurea Receptors; Treatment Outcome
PubMed: 30246418
DOI: 10.1111/dme.13823 -
Frontiers in Endocrinology 2022Congenital hyperinsulinism (CHI), although a rare disease, is an important cause of severe hypoglycemia in early infancy and childhood, causing preventable morbidity and... (Review)
Review
Congenital hyperinsulinism (CHI), although a rare disease, is an important cause of severe hypoglycemia in early infancy and childhood, causing preventable morbidity and mortality. Prompt diagnosis and appropriate treatment is necessary to prevent hypoglycaemia mediated brain damage. At present, the medical treatment of CHI is limited to diazoxide as first line and synthetic somatostatin receptor ligands (SRLs) as second line options; therefore understanding somatostatin biology and treatment perspectives is important. Under healthy conditions, somatostatin secreted from pancreatic islet δ-cells reduces insulin release through somatostatin receptor induced cAMP-mediated downregulation and paracrine inhibition of β- cells. Several SRLs with extended duration of action are now commercially available and are being used off-label in CHI patients. Efficacy remains variable with the present generation of SRLs, with treatment effect often being compromised by loss of initial response and adverse effects such as bowel ischaemia and hepatobiliary dysfunction. In this review we have addressed the biology of the somatostatin system contexualised to CHI. We have discussed the clinical use, limitations, and complications of somatostatin agonists and new and emerging therapies for CHI.
Topics: Biology; Child; Congenital Hyperinsulinism; Diazoxide; Humans; Insulin; Ligands; Receptors, Somatostatin; Somatostatin
PubMed: 36237195
DOI: 10.3389/fendo.2022.921357 -
Pharmacology & Therapeutics Nov 2013Diazoxide has been identified over the past 50years to have a number of physiological effects, including lowering the blood pressure and rectifying hypoglycemia. Today... (Review)
Review
Diazoxide has been identified over the past 50years to have a number of physiological effects, including lowering the blood pressure and rectifying hypoglycemia. Today it is used clinically to treat these conditions. More recently, another important mode of action emerged: diazoxide has powerful protective properties against cardiac ischemia. The heart has intrinsic protective mechanisms against ischemia injury; one of which is ischemic preconditioning. Diazoxide mimics ischemic preconditioning. The purpose of this treatise is to review the literature in an attempt to identify the many effectors of diazoxide and discuss how they may contribute to diazoxide's cardioprotective properties. Particular emphasis is placed on the concentration ranges in which diazoxide affects its different targets and how this compares with the concentrations commonly used to study cardioprotection. It is concluded that diazoxide may have several potential effectors that may potentially contribute to cardioprotection, including KATP channels in the pancreas, smooth muscle, endothelium, neurons and the mitochondrial inner membrane. Diazoxide may also affect other ion channels and ATPases and may directly regulate mitochondrial energetics. It is possible that the success of diazoxide lies in this promiscuity and that the compound acts to rebalance multiple physiological processes during cardiac ischemia.
Topics: Animals; Cardiotonic Agents; Diazoxide; Humans; Insulin-Secreting Cells; KATP Channels; Mitochondria; Myocardial Ischemia; Myocytes, Smooth Muscle; Sarcolemma
PubMed: 23792087
DOI: 10.1016/j.pharmthera.2013.06.007 -
Current Opinion in Endocrinology,... Feb 2014Neonatal hypoglycemia is one of the most common biochemical abnormalities encountered in the newborn. However, controversy remains surrounding its definition and... (Review)
Review
PURPOSE OF REVIEW
Neonatal hypoglycemia is one of the most common biochemical abnormalities encountered in the newborn. However, controversy remains surrounding its definition and management especially in asymptomatic patients.
RECENT FINDINGS
New information has been published that describes the incidence and timing of low glucose concentrations in the groups most at risk for asymptomatic neonatal hypoglycemia. Furthermore, one large prospective study failed to find an association between repetitive low glucose concentrations and poor neurodevelopmental outcomes in preterm infants. But hypoglycemia due to hyperinsulinism, especially genetic causes, continued to be associated with brain injury. New advances were made in the diagnosis and management of hyperinsulinism, including acquired hyperinsulinism in small for gestational age infants and others. Continuous glucose monitoring remains an attractive strategy for future research in this area.
SUMMARY
The fundamental question of how best to manage asymptomatic newborns with low glucose concentrations remains unanswered. Balancing the risks of overtreating newborns with low glucose concentrations who are undergoing a normal transition following birth against the risks of undertreating those in whom low glucose concentrations are pathological, dangerous, and/or a harbinger of serious metabolic disease remains a challenge.
Topics: Biosensing Techniques; Blood Glucose; Developmental Disabilities; Diazoxide; Diuretics; Female; Glucose; Humans; Hydrochlorothiazide; Hyperinsulinism; Hypoglycemia; Infant, Newborn; Infant, Premature; Male; Monitoring, Physiologic; Potassium Chloride; Vasodilator Agents
PubMed: 24275620
DOI: 10.1097/MED.0000000000000027 -
The Western Journal of Medicine May 1980Although drug treatment of hypertension is associated with improved survival and decreased vascular complications, drug compliance is a major problem in the control of... (Review)
Review
Although drug treatment of hypertension is associated with improved survival and decreased vascular complications, drug compliance is a major problem in the control of hypertension. All antihypertensive medications are associated with side effects; thus, it is a physician's responsibility to explain to each patient the side effects of the drugs he prescribes to treat hypertension, and to instill in the patient a sense of necessity for the treatment of hypertension. The choice of antihypertensive drug should be made based on each patient's lifestyle, overall health and ability to tolerate the drug. Ideally, the antihypertensive regimen should be simple, effective, convenient to take and have very few side effects.
Topics: Adolescent; Adult; Antihypertensive Agents; Clonidine; Diazoxide; Diuretics; Guanethidine; Humans; Hydralazine; Hypertension; Methyldopa; Metoprolol; Minoxidil; Nitroprusside; Patient Compliance; Prazosin; Propranolol; Reserpine; Sodium Chloride Symporter Inhibitors
PubMed: 6992462
DOI: No ID Found -
American Journal of Physiology. Heart... Jun 2016
Topics: Adenosine Triphosphate; Diazoxide; Ischemic Preconditioning, Myocardial; KATP Channels
PubMed: 27199122
DOI: 10.1152/ajpheart.00309.2016