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Wang T, Malone J, Fu H, Heilmann C, Qu Y, Huster WJ. Crossover design and its application in late-phase diabetes studies. J Diabetes 2016; 8:610-8. [PMID: 27100270 DOI: 10.1111/1753-0407.12412] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Revised: 04/01/2016] [Accepted: 04/15/2016] [Indexed: 11/30/2022] Open
Abstract
Crossover design has been widely used in late-phase clinical studies, as well as in pharmacokinetic and pharmacodynamic, bioequivalence, and medical device studies; however, its interpretability and applicability continue to be debated. Herein we provide discussions around a crossover design's scientific benefit, applicability, and how it can be implemented in late-phase diabetes studies by properly handling key issues: carryover effect, washout period, and baseline selection. Specifically, detailed considerations are provided about the validity and situations of having appropriate length of study duration to deal with carryover effects so that a washout period may not be needed. A simulation study and data mining results on 12 crossover late-phase insulin clinical trials are presented to examine the discussion points and proposals.
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Affiliation(s)
- Tao Wang
- Eli Lilly and Company, Insulin and Device Development, Indianapolis, Indiana, USA
| | - James Malone
- Eli Lilly and Company, Insulin and Device Development, Indianapolis, Indiana, USA
| | - Haoda Fu
- Eli Lilly and Company, Insulin and Device Development, Indianapolis, Indiana, USA
| | - Cory Heilmann
- Eli Lilly and Company, Insulin and Device Development, Indianapolis, Indiana, USA
| | - Yongming Qu
- Eli Lilly and Company, Insulin and Device Development, Indianapolis, Indiana, USA
| | - William J Huster
- Eli Lilly and Company, Insulin and Device Development, Indianapolis, Indiana, USA
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Bodenlenz M, Ellmerer M, Schaupp L, Jacobsen LV, Plank J, Brunner GA, Wutte A, Aigner B, Mautner SI, Pieber TR. Bioavailability of insulin detemir and human insulin at the level of peripheral interstitial fluid in humans, assessed by open-flow microperfusion. Diabetes Obes Metab 2015; 17:1166-72. [PMID: 26260082 DOI: 10.1111/dom.12551] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Revised: 07/30/2015] [Accepted: 08/06/2015] [Indexed: 11/28/2022]
Abstract
AIMS To find an explanation for the lower potency of insulin detemir observed in humans compared with unmodified human insulin by investigating insulin detemir and human insulin concentrations directly at the level of peripheral insulin-sensitive tissues in humans in vivo. METHODS Euglycaemic-hyperinsulinaemic clamp experiments were performed in healthy volunteers. Human insulin was administered i.v. at 6 pmol/kg/min and insulin detemir at 60 pmol/kg/min, achieving a comparable steady-state pharmacodynamic action. In addition, insulin detemir was doubled to 120 pmol/kg/min. Minimally invasive open-flow microperfusion (OFM) sampling methodology was combined with inulin calibration to quantify human insulin and insulin detemir in the interstitial fluid (ISF) of subcutaneous adipose and skeletal muscle tissue. RESULTS The human insulin concentration in the ISF was ∼115 pmol/l or ∼30% of the serum concentration, whereas the insulin detemir concentration in the ISF was ∼680 pmol/l or ∼2% of the serum concentration. The molar insulin detemir interstitial concentration was five to six times higher than the human insulin interstitial concentration and metabolic clearance of insulin detemir from serum was substantially reduced compared with human insulin. CONCLUSIONS OFM proved useful for target tissue measurements of human insulin and the analogue insulin detemir. Our tissue data confirm a highly effective retention of insulin detemir in the vascular compartment. The higher insulin detemir relative to human insulin tissue concentrations at comparable pharmacodynamics, however, indicate that the lower potency of insulin detemir in humans is attributable to a reduced effect in peripheral insulin-sensitive tissues and is consistent with the reduced in vitro receptor affinity.
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MESH Headings
- Adult
- Biological Availability
- Calibration
- Cross-Over Studies
- Dose-Response Relationship, Drug
- Extracellular Fluid/metabolism
- Glucose Clamp Technique
- Humans
- Hypoglycemic Agents/administration & dosage
- Hypoglycemic Agents/blood
- Hypoglycemic Agents/metabolism
- Hypoglycemic Agents/pharmacokinetics
- Infusions, Intravenous
- Insulin Detemir/administration & dosage
- Insulin Detemir/blood
- Insulin Detemir/metabolism
- Insulin Detemir/pharmacokinetics
- Insulin, Regular, Human/administration & dosage
- Insulin, Regular, Human/blood
- Insulin, Regular, Human/metabolism
- Insulin, Regular, Human/pharmacokinetics
- Inulin/administration & dosage
- Inulin/blood
- Inulin/metabolism
- Inulin/pharmacokinetics
- Lipoylation
- Male
- Metabolic Clearance Rate
- Muscle, Skeletal/metabolism
- Subcutaneous Fat/metabolism
- Tissue Distribution
- Young Adult
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Affiliation(s)
- M Bodenlenz
- HEALTH, Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft m.b.H, Graz, Austria
| | - M Ellmerer
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - L Schaupp
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | | | - J Plank
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - G A Brunner
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - A Wutte
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - B Aigner
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria
- Division of General Dermatology, Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria
| | - S I Mautner
- HEALTH, Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft m.b.H, Graz, Austria
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - T R Pieber
- HEALTH, Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft m.b.H, Graz, Austria
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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Abstract
Maternal metabolism changes substantially during pregnancy, which poses numerous challenges to physicians managing pregnancy in women with diabetes. Insulin is the agent of choice for glycemic control in pregnant women with diabetes, and the insulin analogs are particularly interesting for use in pregnancy. These agents may reduce the risk of hypoglycemia and promote a more physiological glycemic profile than regular human insulin in pregnant women with type 1 (T1D), type 2 (T2D), or gestational (GDM) diabetes. However, there have been concerns regarding potential risk for crossing the placental barrier, mitogenic stimulation, teratogenicity, and embryotoxicity. Insulin lispro protamine suspension (ILPS), an intermediate- to long-acting insulin, has a stable and predictable pharmacological profile, and appears to have a favorable time–action profile and produce desirable basal and postprandial glycemic control. As the binding of insulin lispro is unaffected by the protamine molecule, ILPS is likely to have the same mitogenic and immunogenic potential as insulin lispro. Insulin lispro produces similar outcomes to regular insulin in pregnant women with T1D, T2D, or GDM, does not cross the placental barrier, and is considered a useful treatment option for pregnant women with diabetes. Clinical data support the usefulness of ILPS for basal insulin coverage in non-pregnant patients with T1D or T2D, and suggest that the optimal regimen, in terms of balance between efficacy and hypoglycemic risk, is a once-daily injection, especially in patients with T2D. Available data concerning use of ILPS in pregnant women are currently derived from retrospective analyses that involved, in total, >1200 pregnant women. These analyses suggest that ILPS is at least as safe and effective as neutral protamine Hagedorn insulin. Thus, available experimental and clinical data suggest that ILPS once daily is a safe and effective option for the management of diabetes in pregnant women. Funding: Eli Lilly and Company.
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Derosa G, Franzetti I, Querci F, Romano D, D'Angelo A, Maffioli P. Glucose-lowering effect and glycaemic variability of insulin glargine, insulin detemir and insulin lispro protamine in people with type 1 diabetes. Diabetes Obes Metab 2015; 17:554-559. [PMID: 25694300 DOI: 10.1111/dom.12454] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2014] [Revised: 02/01/2015] [Accepted: 02/16/2015] [Indexed: 11/27/2022]
Abstract
AIM To compare, using a continuous glucose monitoring (CGM) system, the effect on glycaemic variability of insulin glargine, detemir and lispro protamine. METHODS A total of 49 white people with type 1 diabetes, not well controlled by three times daily insulin lispro, taken for at least 2 months before study and on a stable dose, were enrolled. The study participants were randomized to add insulin glargine, detemir or lispro protamine, once daily, in the evening. We used a CGM system, the iPro Digital Recorder (Medtronic MiniMed, Northridge, CA, USA) for 1 week. Glycaemic control was assessed according to mean blood glucose values, the area under the glucose curve above 3.9 mmol/l (AUC(>3.9)) or above 10.0 mmol/l (AUC(>10.0)), and the percentage of time spent with glucose values >3.9 or >10.0 mmol/l. Intraday glycaemic variability was assessed using standard deviation (s.d.) values, the mean amplitude of glycaemic excursions and continuous overlapping of net glycaemic action. Day-to-day glycaemic variability was assessed using the mean of daily differences. RESULTS The s.d. was found to be significantly lower with insulin lispro protamine and glargine compared with insulin detemir. AUC(>3.9) was higher and AUC(>10.0) was lower with insulin lispro protamine and glargine compared with detemir. The mean amplitude of glycaemic excursions and continuous overlapping net glycaemic action values were lower with insulin lispro protamine and glargine compared with detemir. In addition, the mean of daily differences was significantly lower with insulin lispro protamine and glargine compared with detemir. Fewer hypoglycaemic events were recorded during the night-time with insulin lispro protamine compared with glargine and detemir. CONCLUSIONS The results suggest that insulin lispro protamine and glargine are more effective than detemir in reducing glycaemic variability and improving glycaemic control in people with type 1 diabetes. Insulin lispro protamine seems to lead to fewer hypoglycaemic events than other insulin regimens.
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Affiliation(s)
- G Derosa
- Department of Internal Medicine and Therapeutics, Fondazione IRCCS Policlinico S. Matteo, University of Pavia, Pavia, Italy
- Centre for the Study of Endocrine-Metabolic Pathophysiology and Clinical Research, University of Pavia, Pavia, Italy
| | - I Franzetti
- Metabolic Unit, S. Antonio Abate Hospital, Gallarate, Italy
| | - F Querci
- Ospedale Pesenti Fenaroli, Alzano Lombardo, Bergamo, Italy
| | - D Romano
- Department of Internal Medicine and Therapeutics, Fondazione IRCCS Policlinico S. Matteo, University of Pavia, Pavia, Italy
| | - A D'Angelo
- Department of Internal Medicine and Therapeutics, Fondazione IRCCS Policlinico S. Matteo, University of Pavia, Pavia, Italy
| | - P Maffioli
- Department of Internal Medicine and Therapeutics, Fondazione IRCCS Policlinico S. Matteo, University of Pavia, Pavia, Italy
- PhD School in Experimental Medicine, University of Pavia, Pavia, Italy
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Poomalar GK. Changing trends in management of gestational diabetes mellitus. World J Diabetes 2015; 6:284-95. [PMID: 25789109 PMCID: PMC4360421 DOI: 10.4239/wjd.v6.i2.284] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Revised: 10/18/2014] [Accepted: 12/29/2014] [Indexed: 02/05/2023] Open
Abstract
Gestational diabetes mellitus (GDM) is on the rise globally. In view of the increasing prevalence of GDM and fetal and neonatal complications associated with it, there is a splurge of research in this field and management of GDM is undergoing a sea change. Trends are changing in prevention, screening, diagnosis, treatment and future follow up. There is emerging evidence regarding use of moderate exercise, probiotics and vitamin D in the prevention of GDM. Regarding treatment, newer insulin analogs like aspart, lispro and detemir are associated with better glycemic control than older insulins. Continuous glucose monitoring systems and continuous subcutaneous insulin systems may play a role in those who require higher doses of insulin for sugar control. Evidence exists that favors metformin as a safer alternative to insulin in view of good glycemic control and better perinatal outcomes. As the risk of developing GDM in subsequent pregnancies and also the risk of overt diabetes in later life is high, regular assessment of these women is required in future. Lifestyle interventions or metformin should be offered to women with a history of GDM who develop pre-diabetes. Further studies are required in the field of prevention of GDM for optimizing obstetric outcome.
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Rossetti P, Ampudia-Blasco FJ, Ascaso JF. Old and new basal insulin formulations: understanding pharmacodynamics is still relevant in clinical practice. Diabetes Obes Metab 2014; 16:695-706. [PMID: 24401118 DOI: 10.1111/dom.12256] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2013] [Revised: 07/05/2013] [Accepted: 12/20/2013] [Indexed: 12/17/2022]
Abstract
Long-acting insulin analogues have been developed to mimic the physiology of basal insulin secretion more closely than human insulin formulations (Neutral Protamine Hagedorn, NPH). However, the clinical evidence in favour of analogues is still controversial. Although their major benefit as compared with NPH is a reduction in the hypoglycaemia risk, some cost/effectiveness analyses have not been favourable to analogues, largely because of their higher price. Nevertheless, these new formulations have conquered the insulin market. Human insulin represents currently no more than 20% of market share. Despite (in fact because of) the widespread use of insulin analogues it remains critical to analyse the pharmacodynamics (PD) of basal insulin formulations appropriately to interpret the results of clinical trials correctly. Importantly, these data may help physicians in tailoring insulin therapy to patients' individual needs and, additionally, when clinical evidence is not available, to optimize insulin treatment. For patients at low risk for/from hypoglycaemia, it might be acceptable and also cost-effective not to use long-acting insulin analogues as basal insulin replacement. Conversely, in patients with a higher degree of insulin deficiency and increased risk for hypoglycaemia, analogues are the best option due to their more physiological profile, as has been shown in PD and clinical studies. From this perspective optimizing basal insulin treatment, especially in type 2 diabetes patients who are less prone to hypoglycaemia, would be suitable making significant resources available for other relevant aspects of diabetes care.
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MESH Headings
- Chemistry, Pharmaceutical
- Diabetes Mellitus, Type 1/drug therapy
- Diabetes Mellitus, Type 2/drug therapy
- Evidence-Based Medicine
- Humans
- Hypoglycemic Agents/chemistry
- Hypoglycemic Agents/pharmacokinetics
- Hypoglycemic Agents/pharmacology
- Hypoglycemic Agents/therapeutic use
- Insulin, Long-Acting/chemistry
- Insulin, Long-Acting/pharmacokinetics
- Insulin, Long-Acting/pharmacology
- Insulin, Long-Acting/therapeutic use
- Insulin, Short-Acting/chemistry
- Insulin, Short-Acting/pharmacokinetics
- Insulin, Short-Acting/pharmacology
- Insulin, Short-Acting/therapeutic use
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Affiliation(s)
- P Rossetti
- Department of Internal Medicine, Sant Francesc de Borja Hospital, Gandia, Spain
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Zeng S, Baillargeat D, Ho HP, Yong KT. Nanomaterials enhanced surface plasmon resonance for biological and chemical sensing applications. Chem Soc Rev 2014; 43:3426-52. [PMID: 24549396 DOI: 10.1039/c3cs60479a] [Citation(s) in RCA: 546] [Impact Index Per Article: 49.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The main challenge for all electrical, mechanical and optical sensors is to detect low molecular weight (less than 400 Da) chemical and biological analytes under extremely dilute conditions. Surface plasmon resonance sensors are the most commonly used optical sensors due to their unique ability for real-time monitoring the molecular binding events. However, their sensitivities are insufficient to detect trace amounts of small molecular weight molecules such as cancer biomarkers, hormones, antibiotics, insecticides, and explosive materials which are respectively important for early-stage disease diagnosis, food quality control, environmental monitoring, and homeland security protection. With the rapid development of nanotechnology in the past few years, nanomaterials-enhanced surface plasmon resonance sensors have been developed and used as effective tools to sense hard-to-detect molecules within the concentration range between pmol and amol. In this review article, we reviewed and discussed the latest trend and challenges in engineering and applications of nanomaterials-enhanced surface plasmon resonance sensors (e.g., metallic nanoparticles, magnetic nanoparticles, carbon-based nanomaterials, latex nanoparticles and liposome nanoparticles) for detecting "hard-to-identify" biological and chemical analytes. Such information will be viable in terms of providing a useful platform for designing future ultrasensitive plasmonic nanosensors.
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Affiliation(s)
- Shuwen Zeng
- School of Electrical and Electronic Engineering, Nanyang Technological University, Singapore, 639798, Singapore.
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