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Emad-Eldin M, Balata GF, Elshorbagy EA, Hamed MS, Attia MS. Insulin therapy in type 2 diabetes: Insights into clinical efficacy, patient-reported outcomes, and adherence challenges. World J Diabetes 2024; 15:828-852. [PMID: 38766443 PMCID: PMC11099362 DOI: 10.4239/wjd.v15.i5.828] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 02/01/2024] [Accepted: 03/20/2024] [Indexed: 05/10/2024] Open
Abstract
Insulin therapy plays a crucial role in the management of type 2 diabetes as the disease progresses. Over the past century, insulin formulations have undergone significant modifications and bioengineering, resulting in a diverse range of available insulin products. These products show distinct pharmacokinetic and pharmacodynamic profiles. Consequently, various insulin regimens have em-erged for the management of type 2 diabetes, including premixed formulations and combinations of basal and bolus insulins. The utilization of different insulin regimens yields disparate clinical outcomes, adverse events, and, notably, patient-reported outcomes (PROs). PROs provide valuable insights from the patient's perspective, serving as a valuable mine of information for enhancing healthcare and informing clinical decisions. Adherence to insulin therapy, a critical patient-reported outcome, significantly affects clinical outcomes and is influenced by multiple factors. This review provides insights into the clinical effectiveness of various insulin preparations, PROs, and factors impacting insulin therapy adherence, with the aim of enhancing healthcare practices and informing clinical decisions for individuals with type 2 diabetes.
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Affiliation(s)
- Mahmoud Emad-Eldin
- Department of Pharmacy Practice, Faculty of Pharmacy, Zagazig University, Zagazig HFQM+872, Al-Sharqia Governorate, Egypt
| | - Gehan F Balata
- Department of Pharmacy Practice, Faculty of Pharmacy, Heliopolis University, Cairo 44519, Egypt
- Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Al-Sharqia Governorate, Egypt
| | - Eman A Elshorbagy
- Department of Internal Medicine, Faculty of Medicine, Zagazig University, Zagazig 44519, Al-Sharqia Governorate, Egypt
| | - Mona S Hamed
- Department of Community at Faculty of Medicine, Zagazig University, Zagazig 44519, Al-Sharqia Governorate, Egypt
| | - Mohamed S Attia
- Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Al-Sharqia Governorate, Egypt
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Haak T, Gölz S, Fritsche A, Füchtenbusch M, Siegmund T, Schnellbächer E, Klein HH, Uebel T, Droßel D. Therapy for Type 1 Diabetes. Exp Clin Endocrinol Diabetes 2024; 132:125-135. [PMID: 38365208 DOI: 10.1055/a-2166-6695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/18/2024]
Affiliation(s)
- Thomas Haak
- Diabetes Centre Bad Mergentheim, Bad Mergentheim, Germany
| | | | - Andreas Fritsche
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany
| | | | | | | | - Harald H Klein
- Department of Internal Medicine I - General Internal Medicine, Endocrinology and Diabetology, Gastroenterology and Hepatology, Bergmannsheil University Hospitals, Bochum, Germany
| | - Til Uebel
- prima-diab Practice Drs. Uebel/Nittka/Mayer/Merkle, Ittlingen, Germany
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Haak T, Gölz S, Fritsche A, Füchtenbusch M, Siegmund T, Schnellbächer E, Klein HH, Uebel T, Droßel D. Therapie des Typ-1-Diabetes – Kurzfassung der S3-Leitlinie (AWMF-Registernummer: 057-013; 4. Auflage 2018). DIABETOL STOFFWECHS 2023; 18:S136-S147. [DOI: 10.1055/a-2075-9984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Affiliation(s)
- Thomas Haak
- Diabetes-Klinik Bad Mergentheim, Bad Mergentheim, Deutschland
| | - Stefan Gölz
- Diabetesschwerpunktpraxis Esslingen, Esslingen, Deutschland
| | - Andreas Fritsche
- Innere Medizin IV, Medizinische Klinik, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | | | | | | | - Harald H. Klein
- Medizinische Universitätsklinik I – Allgemeine Innere Medizin, Endokrinologie und Diabetologie, Gastroenterologie und Hepatologie, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil, Bochum, Deutschland
| | - Til Uebel
- prima-diab Praxis Dres. Uebel/Nittka/Mayer/Merkle, Ittlingen, Deutschland
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Haak T, Gölz S, Fritsche A, Füchtenbusch M, Siegmund T, Schnellbächer E, Klein HH, Uebel T, Droßel D. Therapie des Typ-1-Diabetes. DIE DIABETOLOGIE 2023; 19:647-657. [DOI: 10.1007/s11428-023-01046-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 03/15/2023] [Indexed: 01/06/2025]
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Haak T, Gölz S, Fritsche A, Füchtenbusch M, Siegmund T, Schnellbächer E, Klein HH, Uebel T, Droßel D. Therapie des Typ-1-Diabetes. DIABETES AKTUELL 2023; 21:30-42. [DOI: 10.1055/a-2012-3827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Affiliation(s)
- Thomas Haak
- Diabetes-Klinik Bad Mergentheim, Bad Mergentheim, Deutschland
| | - Stefan Gölz
- Diabetesschwerpunktpraxis Esslingen, Esslingen, Deutschland
| | - Andreas Fritsche
- Innere Medizin IV, Medizinische Klinik, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | | | | | | | - Harald H. Klein
- Medizinische Universitätsklinik I – Allgemeine Innere Medizin, Endokrinologie und Diabetologie, Gastroenterologie und Hepatologie, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil, Bochum, Deutschland
| | - Til Uebel
- prima-diab Praxis Dres. Uebel/Nittka/Mayer/Merkle, Ittlingen, Deutschland
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Haak T, Gölz S, Fritsche A, Füchtenbusch M, Siegmund T, Schnellbächer E, Klein HH, Uebel T, Droßel D. Therapie des Typ-1-Diabetes. DIABETOL STOFFWECHS 2022; 17:S133-S144. [DOI: 10.1055/a-1916-2101] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Affiliation(s)
- Thomas Haak
- Diabetes-Klinik Bad Mergentheim, Bad Mergentheim, Deutschland
| | - Stefan Gölz
- Diabetesschwerpunktpraxis Esslingen, Esslingen, Deutschland
| | - Andreas Fritsche
- Innere Medizin IV, Medizinische Klinik, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | | | | | | | - Harald H. Klein
- Medizinische Universitätsklinik I – Allgemeine Innere Medizin, Endokrinologie und Diabetologie, Gastroenterologie und Hepatologie, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil, Bochum, Deutschland
| | - Til Uebel
- prima-diab Praxis Dres. Uebel/Nittka/Mayer/Merkle, Ittlingen, Deutschland
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Haak T, Gölz S, Fritsche A, Füchtenbusch M, Siegmund T, Schnellbächer E, Klein HH, Uebel T, Droßel D. Therapie des Typ-1-Diabetes. DIE DIABETOLOGIE 2022; 18:612-622. [DOI: 10.1007/s11428-022-00920-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 05/17/2022] [Indexed: 01/06/2025]
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Haak T, Gölz S, Fritsche A, Füchtenbusch M, Siegmund T, Schnellbächer E, Klein HH, Uebel T, Droßel D. Therapy of Type 1 Diabetes. Exp Clin Endocrinol Diabetes 2022; 130:S39-S48. [PMID: 35373309 DOI: 10.1055/a-1624-3340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
| | | | - Andreas Fritsche
- Department of Internal Medicine IV, University Hospital, Tübingen, Germany
| | | | - Thorsten Siegmund
- Diabetes, Hormones and Metabolism Centre, Private Practice at the Isar Hospital, Munich, Germany
| | | | - Harald H Klein
- Department of Endocrinology and Diabetes, Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum, Bochum, Germany
| | - Til Uebel
- prima-diab Practice Dres. Uebel, Ittlingen, Germany
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Haak T, Gölz S, Fritsche A, Füchtenbusch M, Siegmund T, Schnellbächer E, Klein HH, Uebel T, Droßel D. Therapie des Typ-1-Diabetes. DER DIABETOLOGE 2021; 17:411-421. [DOI: 10.1007/s11428-021-00764-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 04/14/2021] [Indexed: 01/06/2025]
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Similar pharmacokinetics and pharmacodynamics of a new biosimilar and reference insulin aspart in healthy Chinese males. Sci Rep 2021; 11:9495. [PMID: 33947913 PMCID: PMC8096952 DOI: 10.1038/s41598-021-88782-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 03/19/2021] [Indexed: 02/05/2023] Open
Abstract
Insulin aspart (IAsp) is one of the main therapies used to control blood glucose after a meal. This study aimed to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of 2 rapid-acting IAsp products: a new IAsp biosimilar (RD10046) and NovoRapid. In a single-center, randomized, single-dose, 2-period, crossover, euglycemic clamp study (registry number: CTR20180517, registration date: 2018-05-30), healthy Chinese males were randomized to receive 0.2 U/kg of the IAsp biosimilar RD10046 and NovoRapid under fasted conditions on two separate occasions. PK and PD were assessed for up to 10 h. Of the 30 randomized subjects, all 30 completed both treatment periods. The PK (area under the curve [AUC] of total IAsp; maximum observed IAsp concentration [Cmax]) and PD (maximum glucose infusion rate [GIRmax]; total glucose infusion during the clamp [AUCGIR,0–10h]) were similar between the new IAsp biosimilar RD10046 and NovoRapid. In all cases, the 90% CIs for the ratios of the geometric means were completely contained in the prespecified acceptance limits of 0.80–1.25. No hypoglycemic events, allergic reactions, or local injection adverse reactions occurred in this trial. We concluded that the studied IAsp biosimilar (RD10046) was bioequivalent to NovoRapid.
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Demir T, Turan S, Unluhizarci K, Topaloglu O, Tukek T, Gogas Yavuz D. Use of Insulin Degludec/Insulin Aspart in the Management of Diabetes Mellitus: Expert Panel Recommendations on Appropriate Practice Patterns. Front Endocrinol (Lausanne) 2021; 12:616514. [PMID: 33776914 PMCID: PMC7996092 DOI: 10.3389/fendo.2021.616514] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 01/18/2021] [Indexed: 12/20/2022] Open
Abstract
Insulin degludec/insulin aspart (IDegAsp) is a fixed-ratio co-formulation of insulin degludec (IDeg), which provides long-lasting basal insulin coverage, and insulin aspart (IAsp), which targets post-prandial glucose. This expert panel aimed to provide a practical and implementable guidance document to assist clinicians in prescribing IDegAsp in the diabetes management with respect to different patient populations including children and adults with type 1 diabetes (T1D) or type 2 diabetes (T2D) as well as pregnant, elderly and hospitalized patients and varying practice patterns (insulin-naive, insulin-treated, switching from basal, basal bolus and premix regimens). The experts recommended that IDegAsp can be used in insulin-naive T2D patients with poor glycemic control (HbA1c >8.5%) despite optimal oral antidiabetic drugs (OADs) as well as in insulin-treated T2D patients by switching from basal insulin, basal-bolus therapy or premixed insulins in relation to lower risk of nocturnal hypoglycemia, fewer injections and lower intraday glycemic variability, respectively. The experts considered the use of IDegAsp in children with T2D as a basal bolus alternative rather than as an alternative to basal insulin after metformin failure, use of IDegAsp in adult T1D patients as a simplified basal bolus regimen with lesser nocturnal hypoglycemia, fewer injections and better fasting plasma glucose control and in children with T1D as an alternative insulin regimen with fewer injection to increase treatment adherence. The proposed expert opinion provides practical information on use of IDegAsp in different patient populations and practice patterns to assist clinicians, which seems to compensate the need for easily implementable guidance on this novel insulin regimen.
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Affiliation(s)
- Tevfik Demir
- Department of Endocrinology and Metabolism, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey
| | - Serap Turan
- Department Pediatric Endocrinology, Marmara University Faculty of Medicine, Istanbul, Turkey
| | - Kursad Unluhizarci
- Department of Endocrinology and Metabolism, Erciyes University Faculty of Medicine, Kayseri, Turkey
| | - Oya Topaloglu
- Department of Endocrinology and Metabolism, Ankara Yildirim Beyazit University Faculty of Medicine, Ankara City Hospital, Ankara, Turkey
| | - Tufan Tukek
- Department of Endocrinology and Metabolism, Istanbul University Istanbul Faculty of Medicine, Istanbul, Turkey
| | - Dilek Gogas Yavuz
- Department of Endocrinology and Metabolism, Marmara University Faculty of Medicine, Istanbul, Turkey
- *Correspondence: Dilek Gogas Yavuz,
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Haak T, Gölz S, Fritsche A, Füchtenbusch M, Siegmund T, Schnellbächer E, Klein HH, Uebel T, Droßel D. Therapie des Typ-1-Diabetes – Kurzfassung der S3-Leitlinie (AWMF-Registernummer: 057-013; 2. Auflage). DIABETOL STOFFWECHS 2020. [DOI: 10.1055/a-1193-3724] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Affiliation(s)
| | | | - Andreas Fritsche
- Innere Medizin IV, Medizinische Klinik, Universitätsklinikum Tübingen
| | | | | | | | - Harald H. Klein
- Medizinische Universitätsklinik I – Allgemeine Innere Medizin, Endokrinologie und Diabetologie, Gastroenterologie und Hepatologie, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil
| | - Til Uebel
- prima-diab Praxis Dres. Uebel/Nittka/Mayer/Merkle, Ittlingen
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Mehta R, Chen R, Hirose T, John M, Kok A, Lehmann R, Unnikrishnan AG, Yavuz DG, Fulcher G. Practical use of insulin degludec/insulin aspart in a multinational setting: beyond the guidelines. Diabetes Obes Metab 2020; 22:1961-1975. [PMID: 32618405 PMCID: PMC7689716 DOI: 10.1111/dom.14128] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 06/17/2020] [Accepted: 06/26/2020] [Indexed: 12/17/2022]
Abstract
Insulin degludec/insulin aspart (IDegAsp) is a fixed-ratio co-formulation of insulin degludec, which provides long-lasting basal insulin coverage, and insulin aspart, which targets postprandial glycaemia. This review provides expert opinion on the practical clinical use of IDegAsp, including: dose timings relative to meals, when and how to intensify treatment from once-daily (OD) to twice-daily (BID) dose adjustments, and use in special populations (including hospitalized patients). IDegAsp could be considered as one among the choices for initiating insulin treatment, preferential to starting on basal insulin alone, particularly for people with severe hyperglycaemia and/or when postprandial hyperglycaemia is a major concern. The recommended starting dose of IDegAsp is 10 units with the most carbohydrate-rich meal(s), followed by individualized dose adjustments. Insulin doses should be titrated once weekly in two-unit steps, guided by individualized fasting plasma glucose targets and based on patient goals, preferences and hypoglycaemia risk. Options for intensification from IDegAsp OD are discussed, which should be guided by HbA1c, prandial glucose levels, meal patterns and patient preferences. Recommendations for switching to IDegAsp from basal insulin, premixed insulins OD/BID, and basal-plus/basal-bolus regimens are discussed. IDegAsp can be co-administered with other antihyperglycaemic drugs; however, sulphonylureas frequently need to be discontinued or the dose reduced, and the IDegAsp dose may need to be decreased when sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists are added. Considerations around the initiation or continuation of IDegAsp in hospitalized individuals are discussed, as well as in those undergoing medical procedures.
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Affiliation(s)
- Roopa Mehta
- Unidad de Investigación en Enfermedades Metabólicas, Departamento de Endocrinología y MetabolismoInstituto Nacional de Ciencias Médicas y Nutrición Salvador ZubiránMexico CityMexico
| | - Roger Chen
- Department of EndocrinologySt Vincentʼs HospitalSydneyAustralia
- University of New South Wales, Office of Medical EducationUniversity of SydneySydneyAustralia
| | - Takahisa Hirose
- Division of Diabetes, Metabolism and Endocrinology, Department of MedicineToho University School of MedicineTokyoJapan
| | - Mathew John
- Providence Endocrine and Diabetes Specialty CentreThiruvananthapuramKeralaIndia
| | - Adri Kok
- Netcare Union and Clinton HospitalsAlbertonSouth Africa
- University of WitwatersrandJohannesburgSouth Africa
| | - Roger Lehmann
- Department of EndocrinologyUniversity Hospital ZurichZurichSwitzerland
| | | | - Dilek Gogas Yavuz
- Department of Endocrinology and MetabolismMarmara University School of MedicineIstanbulTurkey
| | - Gregory Fulcher
- Northern Clinical SchoolUniversity of SydneySydneyAustralia
- Department of Diabetes, Endocrinology & MetabolismRoyal North Shore Hospital, University of SydneySydneyAustralia
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Kapitza C, Nosek L, Schmider W, Teichert L, Nowotny I. Single-Dose Euglycemic Clamp Study Demonstrating Pharmacokinetic and Pharmacodynamic Similarity Between SAR341402 Insulin Aspart and US- and EU-Approved Versions of Insulin Aspart in Subjects with Type 1 Diabetes. Diabetes Technol Ther 2020; 22:278-284. [PMID: 31825248 PMCID: PMC7104901 DOI: 10.1089/dia.2019.0351] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Background: The objective of this study was to demonstrate the pharmacokinetic and pharmacodynamic similarity among SAR341402 insulin aspart biosimilar/follow-on product, United States-sourced insulin aspart (NovoLog®), and European Union-sourced insulin aspart (NovoRapid®). Materials and Methods: This was a single-center, randomized, double-blind, 3-treatment, 3-period, single-dose, crossover euglycemic study (NCT03202875) in 30 adult male subjects with type 1 diabetes (T1D). Subjects received 0.3 U/kg of each treatment under fasted conditions and underwent a 12-h euglycemic clamp technique to assess pharmacokinetic and pharmacodynamic activity for up to 12 h. Primary endpoints were area under the plasma insulin concentration-time curve from time zero to the last quantifiable concentration (INS-AUClast), and extrapolated to infinity (INS-AUCinf), maximum plasma insulin concentration (INS-Cmax), and the area under the body weight-standardized glucose infusion rate (GIR)-time curve from 0 to 12 hours (GIR-AUC0-12h) among the three treatments. GIRmax was the main secondary endpoint. Results: Of the 30 subjects randomized, 29 completed all 3 treatment periods. Pharmacokinetic and pharmacodynamic profiles were similar in all groups. The extent of exposure (INS-Cmax, INS-AUClast, and INS-AUCinf) and glucodynamic activity (GIR-AUC0-12h, GIRmax) was similar among the three treatments. The corresponding 90% confidence intervals for pairwise treatment ratios were completely contained within the limits of 80%-125%. SAR341402 was well tolerated. Conclusions: The present study demonstrated similar pharmacokinetic exposure profiles and glucodynamic potency among SAR341402, NovoLog, and NovoRapid in subjects with T1D, supporting further clinical evaluation of SAR341402 as a biosimilar/follow-on product.
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Affiliation(s)
| | - Leszek Nosek
- Profil Institut für Stoffwechselforschung GmbH, Neuss, Germany
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Shi C, Sun L, Bai R, Wang H, Liu D, Du J. Comparison of a twice daily injection of insulin aspart 50 with insulin aspart 30 in patients with poorly controlled type 2 diabetes. Curr Med Res Opin 2019; 35:1091-1096. [PMID: 30550344 DOI: 10.1080/03007995.2018.1558853] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
OBJECTIVE To compare the efficacy and safety of a twice daily injection of insulin aspart (BIAsp) 30 and BIAsp50 in patients with type 2 diabetes mellitus (T2DM) poorly controlled with oral hypoglycemic agents (OHAs). METHODS In this 12 week prospective, randomized, parallel trial, a total of 80 T2DM patients, 59 ± 10 years old with a disease duration of 9.3 ± 6.6 years and HbA1c >7% despite large doses of metformin and sulfonylurea administration, were randomized to receive BIAsp30 (n = 40) or BIAsp50 (n = 40). The primary endpoint was a change in HbA1c at week 12. RESULTS The changes in HbA1c from baseline were -2.5% ± 1.0% in the BIAsp50 group and -2.5% ± 1.2% in the BIAsp30 group (p = .897). No difference was observed in the rate of HbA1c target achievement (<7.0%) between BIAsp50 (42.5%) and BIAsp30 (32.5%) (p = .495). The change in fasting plasma glucose (FPG) in the BIAsp50 group was lower than that in the BIAsp30 group (p < .001), while the change in two-hour postprandial blood glucose (2hPBG) was higher and blood glucose excursion was lower in the BIAsp50 group than that in the BIAsp30 group (p < .001, p < .001). A significant improvement in HbA1c was observed with BIAsp50 in subgroups with baseline blood glucose excursion >7.8 mmol/L or 2hPBG >17.6 mmol/L compared with BIAsp30. There were no differences in hypoglycemia or body weight between groups. CONCLUSIONS Compared with BIAsp30, BIAsp50 showed greater efficacy in patients with baseline BG excursion >7.8 mmol/L or 2hPBG >17.6 mmol/L as well as good safety for hypoglycemia. CLINICAL TRIAL REGISTRATION ChiCTR-IIR-16008958.
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Affiliation(s)
- Chunhong Shi
- a Department of Endocrinology , The First Affiliated Hospital of Dalian Medical University , Dalian , PR China
| | - Luyan Sun
- a Department of Endocrinology , The First Affiliated Hospital of Dalian Medical University , Dalian , PR China
| | - Ran Bai
- a Department of Endocrinology , The First Affiliated Hospital of Dalian Medical University , Dalian , PR China
| | - Hao Wang
- a Department of Endocrinology , The First Affiliated Hospital of Dalian Medical University , Dalian , PR China
| | - Dan Liu
- a Department of Endocrinology , The First Affiliated Hospital of Dalian Medical University , Dalian , PR China
| | - Jianling Du
- a Department of Endocrinology , The First Affiliated Hospital of Dalian Medical University , Dalian , PR China
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Haak T, Gölz S, Fritsche A, Füchtenbusch M, Siegmund T, Schnellbächer E, Klein HH, Uebel T, Droßel D. Therapie des Typ-1-Diabetes. DIABETOLOGE 2019. [DOI: 10.1007/s11428-019-0458-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Chou WY, Li YR, Chan WK, Chen ST. Association of diabetic ketoacidosis, severe hypoglycemia and glycemic control among children and young adults with type 1 diabetes mellitus treated with premixed versus basal-bolus insulin therapy. Biomed J 2019; 41:348-355. [PMID: 30709576 PMCID: PMC6363560 DOI: 10.1016/j.bj.2018.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 10/17/2018] [Accepted: 10/19/2018] [Indexed: 10/27/2022] Open
Abstract
BACKGROUND This study compared event rates of diabetic ketoacidosis (DKA) and severe hypoglycemia, as well as glycemic control, among children, adolescents, and young adults with type 1 diabetes mellitus (T1DM) receiving basal-bolus or premixed insulin therapy. METHODS A total of 825 individuals aged ≤ 20 years with T1DM, using either basal-bolus or premixed insulin regimens, were retrospectively recruited from 2001 to 2015. Rates of DKA after diagnosis, severe hypoglycemia, and the level of glycated hemoglobin A1c (HbA1c) improvement during the follow-up period were analyzed. RESULTS Of the 825 patients, 226 receiving a premixed regimen were matched to the same number of patients receiving a basal-bolus regimen. In the matched cohort, DKA (10.62% vs. 5.31%; p = 0.037) and severe hypoglycemic episodes (25.22% vs. 10.62%; p < 0.001) were significantly higher in patients receiving a premixed regimen than those receiving a basal-bolus regimen. The median reduction of HbA1c, compared to the treatment-naive level, was better with the basal-bolus regimen than with the premixed regimen in both matched (2.2 vs. 2.1; p = 0.034) and the entire (3.1 vs. 1.9; p < 0.001) cohorts. Regardless of insulin regimen, a higher HbA1c level was significantly linked to higher risk of DKA development (hazard ratio [HR] 1.35 per 1% increase; p < 0.001) once the HbA1c level was ≥7.5%. CONCLUSIONS A premixed insulin regimen may increase the DKA occurrence rate and severe hypoglycemic risk in children, adolescents, and young adults with TIDM, compared to a basal-bolus regimen. Tight glycemic control with HbA1c < 7.5% may prevent the increased risk of DKA.
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Affiliation(s)
- Wei-Yu Chou
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yan-Rong Li
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wai Kin Chan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Szu-Tah Chen
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
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Fujimoto K, Iwakura T, Aburaya M, Matsuoka N. Twice-daily insulin degludec/insulin aspart effectively improved morning and evening glucose levels and quality of life in patients previously treated with premixed insulin: an observational study. Diabetol Metab Syndr 2018; 10:64. [PMID: 30127860 PMCID: PMC6097398 DOI: 10.1186/s13098-018-0366-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 08/12/2018] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Previous studies comparing insulin degludec/insulin aspart (IDegAsp) with premixed insulin twice daily among insulin users with type 2 diabetes have not thoroughly investigated differences in the glucose variability and psychological evaluations related to insulin regimen changes. We investigated changes in the daily and day-to-day glucose variability and quality of life (QOL) related to insulin use in patients with type 2 diabetes during a switch from premixed insulin preparations comprising either human insulin (BHI30) or insulin aspart (BIAsp30) to IDegAsp twice daily. METHODS In this prospective observational study, 22 subjects (BHI30:BIAsp30 = 12:10) self-measured their blood glucose levels every morning, and before and after all meals each week. Premixed insulin was administered for the first 2 months, followed by IDegAsp for the next 2 months. Efficacy measures were evaluated during the last month or last day of both phases. RESULTS The mean blood glucose levels (175.5 vs. 163.0 mg/dL; P = 0.004) and the M-values (53.9 vs. 27.6; P = 0.049) were significantly lower in the IDegAsp phase. However, no differences in the standard deviations of morning fasting glucose levels were observed between phases (premixed vs. IDegAsp, 20.0 vs. 19.3 mg/dL; P = 0.343). Compared to the premixed phase, the before-breakfast (145.3 vs. 126.0 mg/dL; P < 0.001), after-breakfast (190.3 vs. 170.7 mg/dL; P = 0.001), before-dinner (153.0 vs. 140.1 mg/dL; P = 0.007), and after-dinner glucose levels (198.7 vs. 181.4 mg/dL; P = 0.018) were lower in the IDegAsp phase. However, the before-lunch (150.8 vs. 148.2 mg/dL; P = 0.329) and after-lunch glucose levels (214.7 vs. 211.4 mg/dL; P = 0.308) did not significantly differ between phases. Regarding QOL, the total and therapy-related feeling Insulin Therapy Related-QOL (ITR-QOL) questionnaire scores favored IDegAsp, as did the ITR-QOL at Night questionnaire subscale score of glycemic control before breakfast. CONCLUSIONS Although the day-to-day variability of morning fasting glucose levels did not change, switching to IDegAsp improved daily glucose level variability, the morning and evening glucose control and QOL among patients treated with premixed insulin.Trial registration University Hospital Medical Information Network Clinical Trials Registry, UMIN000021939. Prospectively registered 18 April 2016.
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Affiliation(s)
- Kanta Fujimoto
- Department of Diabetes and Endocrinology, Kobe City Medical Center General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe, 6500047 Japan
| | - Toshio Iwakura
- Department of Diabetes and Endocrinology, Kobe City Medical Center General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe, 6500047 Japan
| | - Megumi Aburaya
- Department of Pharmacy, Kobe City Medical Center General Hospital, Kobe, Japan
| | - Naoki Matsuoka
- Department of Diabetes and Endocrinology, Kobe City Medical Center General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe, 6500047 Japan
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Haahr H, Fita EG, Heise T. A Review of Insulin Degludec/Insulin Aspart: Pharmacokinetic and Pharmacodynamic Properties and Their Implications in Clinical Use. Clin Pharmacokinet 2017; 56:339-354. [PMID: 27696221 PMCID: PMC5340839 DOI: 10.1007/s40262-016-0455-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Insulin degludec/insulin aspart (IDegAsp; 70 % IDeg and 30 % IAsp) is a soluble combination of two individual insulin analogues in one product, designed to provide mealtime glycaemic control due to the IAsp component and basal glucose-lowering effect from the IDeg component. The pharmacokinetic and pharmacodynamic characteristics of IDegAsp have been investigated in a series of clinical pharmacology studies with generally comparable designs, methodologies and patient inclusion/exclusion criteria. The glucose-lowering effect profile of IDegAsp during once-daily dosing at steady state shows distinct and clearly separated action from the prandial and basal components of IDegAsp. The IAsp component provides rapid onset and peak glucose-lowering effect followed by a flat glucose-lowering effect lasting beyond 30 h due to IDeg. During twice-daily dosing, the distinct peak effect and the flat basal effect are retained following each dose. The pharmacological properties of IDegAsp are maintained in the elderly, children, adolescents, Japanese patients and those with hepatic or renal impairment. The potential clinical benefits associated with the pharmacological properties of IDegAsp have been verified in phase III clinical trials comparing IDegAsp with three other currently available treatment options: premixed insulin, basal-bolus regimens and basal-only therapy. IDegAsp shows favourable clinical benefits compared with biphasic insulin aspart 30 and is a viable alternative to basal-bolus and basal-only therapy. This review presents the results from clinical pharmacology studies conducted with IDegAsp to date, and extrapolates these results to clinical use of IDegAsp in the context of findings from the IDegAsp clinical therapeutic studies.
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Affiliation(s)
- Hanne Haahr
- Clinical Pharmacology, Novo Nordisk A/S, Vandtårnsvej 114, 2860, Søborg, Denmark.
| | - Edmond G Fita
- Global Medical Affairs, Novo Nordisk A/S, Vandtårnsvej 114, 2860, Søborg, Denmark
| | - Tim Heise
- Profil Institut für Stoffwechselforschung GmbH, Hellersbergstrasse 9, 41460, Neuss, Germany
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Heise T, Zijlstra E, Nosek L, Heckermann S, Plum-Mörschel L, Forst T. Euglycaemic glucose clamp: what it can and cannot do, and how to do it. Diabetes Obes Metab 2016; 18:962-72. [PMID: 27324560 DOI: 10.1111/dom.12703] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 06/05/2016] [Accepted: 06/06/2016] [Indexed: 01/20/2023]
Abstract
The hyperinsulinaemic-euglycaemic glucose clamp has always been regarded as the "gold standard" for the assessment of pharmacodynamic (PD) properties of insulin preparations; however, there has been controversy over a variety of methodogical details, such as study population, dosing time and the initial stabilization of blood glucose (BG) concentrations at the clamp target level, among clamp groups. As the impact of these details on PD results is unclear, the present review provides an overview of different methodological approaches for both the manual and the automated hyperinsulinaemic-euglycaemic glucose clamp. The advantages and limitations of several methodological details are discussed as well as the relevance of clamp results for the prediction of clinical outcomes. Overall, the best method strongly depends on the exact objective of the trial. If, for instance, duration of action is the primary objective, studies should be carried out in patients with type 1 diabetes to avoid any interference of endogenous insulin. This is less important for variables such as onset of action or early metabolic activity. The hyperinsulinaemic-euglycaemic glucose clamp has a high sensitivity to detect even minor differences between different insulin preparations. The practical relevance of potential differences, however, needs to be investigated in clinical studies. A major prerequisite for obtaining reliable glucose clamp results is the attainment of high clamp quality (i.e. keeping BG concentrations close to the clamp target throughout the experiments). Unfortunately, measures of clamp quality are often under-reported, as is the variability in PD profiles, although these might explain some unconfirmed extreme results obtained in a few clamp studies.
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21
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Bakchoul T, Jouni R, Warkentin TE. Protamine (heparin)-induced thrombocytopenia: a review of the serological and clinical features associated with anti-protamine/heparin antibodies. J Thromb Haemost 2016; 14:1685-95. [PMID: 27378603 DOI: 10.1111/jth.13405] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Indexed: 01/04/2023]
Abstract
Protamine is widely used in medicine as a rapidly-acting antidote to heparin, particularly for reversing heparin anticoagulation after cardiac surgery. Protamine is also used as a stabilizing additive to certain preparations of insulin. Recent reports demonstrate that protamine and heparin form multimolecular complexes that result in high rates of immunization in post-cardiac surgery patients, particularly of immunoglobulin G (IgG) class antibodies; a subset of these anti-protamine/heparin IgG antibodies activates platelets through their FcγIIA (IgG) receptors. Although the clinical consequences of anti-protamine/heparin antibodies that are newly generated after cardiac surgery are unknown, there is evidence that platelet-activating anti-protamine/heparin antibodies already present at the time of cardiac surgery might occasionally explain more severe thrombocytopenia with delayed platelet count recovery, as well as thromboembolic complications, in the post-cardiac surgery setting. Triggers for such antibodies remain poorly-defined, but could include preoperative administration of heparin to diabetic patients receiving protamine-insulin as well as recent previous cardiac surgery. Anti-protamine/heparin antibodies have several features in common with anti-platelet factor 4 (PF4) PF4/heparin antibodies implicated in heparin-induced thrombocytopenia (HIT), including immunization by heparin-containing multimolecular complexes, predominant IgG class, pathological platelet-activating properties, relatively rapid IgG formation without IgM precedence, and antibody transience. Despite these similarities, the risk of anti-protamine/heparin antibody-mediated complications seems to affect the early post-cardiac surgery period, whereas HIT usually occurs at least 5 days following cardiac surgery. Clinicians need to become aware of this recently recognized immunohematological disorder, and research is needed to identify triggers of immunization, improve detection of pathological antibodies and identify patients at risk of this complication.
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Affiliation(s)
- T Bakchoul
- Institute for Immunology and Transfusion Medicine, Universitätsmedizin Greifswald, Greifswald, Germany. ,
| | - R Jouni
- Institute for Immunology and Transfusion Medicine, Universitätsmedizin Greifswald, Greifswald, Germany
| | - T E Warkentin
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
- Department of Medicine, McMaster University, Hamilton, ON, Canada
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Giugliano D, Sieradzki J, Stefanski A, Gentilella R. Personalized intensification of insulin therapy in type 2 diabetes - does a basal-bolus regimen suit all patients? Curr Med Res Opin 2016; 32:1425-34. [PMID: 27126277 DOI: 10.1080/03007995.2016.1181051] [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] [Indexed: 02/02/2023]
Abstract
Many patients with type 2 diabetes mellitus (T2DM) require insulin therapy. If basal insulin fails to achieve glycemic control, insulin intensification is one possible treatment intensification strategy. We summarized clinical data from randomized clinical trials designed to compare the efficacy and safety of basal-bolus and premixed insulin intensification regimens. We defined a between-group difference of ≥0.3% in end-of-study glycated hemoglobin (HbA1c) as clinically meaningful. A PubMed database search supplemented by author-identified papers yielded 15 trials which met selection criteria: randomized design, patients with T2DM receiving basal-bolus (bolus injection ≤3 times/day) vs. premixed (≤3 injections/day) insulin regimens, primary/major endpoint(s) HbA1c- and/or hypoglycemia-related, and trial duration ≥12 weeks. Glycemic control improved with both basal-bolus and premixed insulin regimens with - in most cases - acceptable levels of weight gain and hypoglycemia. A clinically meaningful difference between regimens in glycemic control was recorded in only four comparisons, all of which favored basal-bolus therapy. The incidence of hypoglycemia was significantly different between regimens in only three comparisons, one of which favored premixed insulin and two basal-bolus therapy. Of the four trials that reported a significant difference between regimens in bodyweight change, two favored basal-bolus therapy and two favored premixed insulin. Thus, on a population level, neither basal-bolus therapy nor premixed insulin showed a consistent advantage in terms of glycemic control, hypoglycemic risk, or bodyweight gain. It is therefore recommended that clinicians should adopt an individualized approach to insulin intensification - taking into account the benefits and risks of each treatment approach and the attitude and preferences of each patient - in the knowledge that both basal-bolus and premixed regimens may be successful.
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Affiliation(s)
- D Giugliano
- a Department of Medical, Surgical, Neurological, Metabolic Sciences and Aging , Second University of Naples , Naples , Italy
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23
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Franek E, Haluzík M, Canecki Varžić S, Sargin M, Macura S, Zacho J, Christiansen JS. Twice-daily insulin degludec/insulin aspart provides superior fasting plasma glucose control and a reduced rate of hypoglycaemia compared with biphasic insulin aspart 30 in insulin-naïve adults with Type 2 diabetes. Diabet Med 2016; 33:497-505. [PMID: 26435365 PMCID: PMC5063147 DOI: 10.1111/dme.12982] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/29/2015] [Indexed: 11/17/2022]
Abstract
AIM To evaluate the efficacy and safety of twice-daily insulin degludec/insulin aspart vs. twice-daily biphasic insulin aspart 30 in people with Type 2 diabetes mellitus who were naïve to insulin. METHODS In this 26-week, multinational, open-label, controlled, two-arm, parallel-group, treat-to-target trial, participants [mean (± sd) age 58.9 (±8.9) years, duration of diabetes 9.5 (±5.9) years, HbA1c 68 (±8.7) mmol/mol or 8.4 (±0.8)% and BMI 31.2 (±4.2) kg/m(2) ) were randomized (1:1) to insulin degludec/insulin aspart (n = 197) or biphasic insulin aspart 30 (n = 197), administered with breakfast and the main evening meal, titrated to a self-monitored plasma glucose target > 3.9 and ≤ 5.0 mmol/l. RESULTS The mean HbA1c was reduced to 49 mmol/mol (6.6%) with insulin degludec/insulin aspart and 48 mmol/mol (6.5%) with biphasic insulin aspart 30. Insulin degludec/insulin aspart achieved the prespecified non-inferiority margin (estimated treatment difference 0.02%; 95% CI -0.12, 0.17). Insulin degludec/insulin aspart was superior in lowering fasting plasma glucose (estimated treatment difference -1.00 mmol/l; 95% CI -1.4, -0.6; P < 0.001) and reducing overall and nocturnal confirmed hypoglycaemia at a similar overall insulin dose compared with biphasic insulin aspart 30. Similar proportions of participants in each arm experienced severe hypoglycaemia. Adverse events were equally distributed. CONCLUSIONS Consistent with previous findings, insulin degludec/insulin aspart twice daily effectively improved long-term glycaemic control, with superior reductions in FPG, and significantly less overall and nocturnal confirmed hypoglycaemia compared with biphasic insulin aspart 30 in people with Type 2 diabetes who were insulin-naïve.
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Affiliation(s)
- E Franek
- Mossakowski Medical Research Centre, Polish Academy of Sciences and Department of Internal Diseases, Endocrinology and Diabetology, Central Clinical Hospital MSW, Warsaw, Poland
| | - M Haluzík
- Third Department of Medicine, First Faculty of Medicine and General University Hospital, Charles University, Prague, Czech Republic
| | | | - M Sargin
- Kartal Training and Research Hospital, Istanbul, Turkey
| | - S Macura
- Novo Nordisk A/S, Søborg, Denmark
| | - J Zacho
- Novo Nordisk A/S, Søborg, Denmark
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24
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Haahr H, Sasaki T, Bardtrum L, Ikushima I. Insulin degludec/insulin aspart in Japanese patients with type 1 diabetes mellitus: Distinct prandial and basal glucose-lowering effects. J Diabetes Investig 2016; 7:574-80. [PMID: 27181070 PMCID: PMC4931208 DOI: 10.1111/jdi.12461] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Revised: 11/20/2015] [Accepted: 12/10/2015] [Indexed: 11/28/2022] Open
Abstract
AIMS/INTRODUCTION Insulin degludec/insulin aspart (IDegAsp) is a soluble co-formulation of long-acting insulin degludec (IDeg) and rapid-acting insulin aspart (IAsp). The present study investigated the pharmacodynamic properties of IDegAsp in Japanese patients with type 1 diabetes mellitus. MATERIALS AND METHODS In this randomized, double-blind, two-period, cross-over trial, 21 Japanese patients with type 1 diabetes mellitus received single doses of 0.5 U/kg IDegAsp and biphasic insulin aspart 30 in a randomized sequence (13-21 days washout between treatments). The pharmacodynamic response was evaluated in a 26-h euglycemic glucose clamp (target 5.5 mmol/L). Single-dose IDegAsp glucose infusion rate (GIR) profiles were extrapolated to steady state using modeling. RESULTS The IDegAsp single-dose GIR profile showed a clear distinction between the effects of the bolus (IAsp) and basal (IDeg) components in IDegAsp. When simulated to steady state, the GIR profile of IDegAsp was shifted upwards compared with the single-dose profile, and showed a rapid onset of action and a distinct peak from the IAsp component followed by a separate and sustained basal action from the long-acting IDeg component. For biphasic insulin aspart 30, the initial shape of the GIR profile was similar to IDegAsp, but GIR continuously decreased from maximum and reached zero 18-20 h post-dosing. The characteristics of the GIR profile for IDegAsp were retained when simulated to steady state in a twice-daily dosing regimen. DISCUSSION In Japanese patients with type 1 diabetes mellitus, the pharmacodynamic profile of IDegAsp is characterized by distinct prandial and basal effects from the IAsp and IDeg components, consistent with what has been reported previously in Caucasian patients with type 1 diabetes mellitus.
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25
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Shehadeh N, Maor Y. Effect of a new insulin treatment regimen on glycaemic control and quality of life of Muslim patients with type 2 diabetes mellitus during Ramadan fast - an open label, controlled, multicentre, cluster randomised study. Int J Clin Pract 2015; 69:1281-8. [PMID: 26234442 DOI: 10.1111/ijcp.12695] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 06/06/2015] [Indexed: 11/28/2022] Open
Abstract
We performed a non-inferiority trial comparing insulin detemir (Levemir) and biphasic insulin (NovoMix70) to standard care during Ramadan fast in insulin treated type 2 diabetes mellitus (T2DM) patients. This was an open label, controlled, multicentre, cluster randomised non-inferiority study. Insulin treated T2DM patients from 12 randomly selected primary clinics received Levemir and NovoMix 70 (intervention, n = 127) or standard care according to the American Diabetes Association recommendations (control, n = 118). Insulin dose (intervention) was 60% of the usual, of this 40% was dosed as Levemir at sunrise and 60% as NovoMix 70 before dinner. Insulin was titrated according to daily 4 point self-measured blood glucose (4P-SMBG) levels. The primary outcome was the difference in mean daily 4P-SMBG during days 23-30 of treatment. Mean age was 60.1 (SD 8.9) and 59.4 (SD 10.1) years in the intervention and control respectively. Mean HbA1c was 8.38% (68 mmol/mol) (SD 0.96) and 8.45% (69 mmol/mol) (SD 1.08). Mean BMI was 32.99 (SD 7.05) and 33.08 (SD 7.24), respectively. The intervention was non-inferior to standard care as assessed by mean 4P-SMBG during days 23-30 of treatment [155 (SD 30.76) mg% and 159 (SD 33.24) mg% respectively, p = 0.269]. Adverse event rate was significantly lower in the intervention group [0.04 (SD 0.06) vs. 0.07 (SD 0.11), p = 0.010]. In particular, hypoglycaemia event rate was lower in the intervention group [0.00 (SD 0.01) vs. 0.01 (SD 0.03), p ≤ 0.001]. To conclude, treatment with Levemir and NovoMix 70 was non-inferior to standard care in this heterogeneous group of patients and was associated with less adverse events.
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Affiliation(s)
- N Shehadeh
- Diabetes Clinic, Clalit Medical Services and the Bruce Rappaport Faculty of Medicine, Haifa, Israel
| | - Y Maor
- Infectious Disease Unit, Wolfson Medical Center, Tel Aviv University, Holon, Israel
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Grieshaber P, Bakchoul T, Wilhelm J, Wagner A, Wollbrück M, Böning A, Sachs U. Platelet-activating protamine-heparin-antibodies lead to higher protamine demand in patients undergoing cardiac surgery. J Thorac Cardiovasc Surg 2015; 150:967-73.e1. [PMID: 26298870 DOI: 10.1016/j.jtcvs.2015.07.057] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Revised: 05/14/2015] [Accepted: 07/16/2015] [Indexed: 12/27/2022]
Abstract
OBJECTIVES Platelet-activating antibodies against protamine-heparin-complexes were described in patients undergoing cardiac surgery, but their clinical consequences remain unclear. This prospective single-center observational study aimed to describe the prevalence and clinical consequences of protamine-heparin-complex antibodies in patients undergoing cardiac surgery with cardiopulmonary bypass. METHODS A total of 200 patients undergoing cardiac surgery with cardiopulmonary bypass were included. Blood samples were collected preoperatively and 1 hour, 24 hours, and 7 days after weaning from cardiopulmonary bypass. All sera were tested for the presence of protamine-heparin-complex antibodies using a modified heparin-induced platelet-activation assay. Specific Fcγ receptor IIa-dependent platelet activation was confirmed by repeated testing in the presence of the Fcγ receptor IIa-blocking antibody IV.3. RESULTS Samples from 185 patients were obtained, of whom 24 patients (13%) were positive for protamine-heparin-complex antibodies preoperatively. In all positive samples, functional reactivity was reversible in the presence of IV.3. Although patients with a preoperative presence of protamine-heparin-complex antibodies were significantly older compared with patients negative for protamine-heparin-complex antibodies (73 ± 9.8 years vs 68 ± 10 years, P = .037), no other potential risk factors were identified at 1 day before operation. Patients with protamine-heparin-complex antibodies required significantly more protamine to neutralize heparin (47.66 mg vs 41.67 mg, P = .027). Protamine-heparin-complex antibodies have no significant influence on perioperative platelet numbers, bleeding complications, transfusion requirement, thromboembolic events, major cardiovascular and cerebrovascular events, inflammation parameters, or kidney function. CONCLUSIONS Protamine-heparin-complex antibodies occur frequently in patients undergoing cardiac surgery on cardiopulmonary bypass, resulting in specific platelet activation in vitro. Protamine-heparin-complex antibodies are associated with increased protamine requirement after cardiopulmonary bypass and possibly slower recovery of platelet numbers.
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Affiliation(s)
- Philippe Grieshaber
- Department of Adult and Pediatric Cardiovascular Surgery, University Hospital Giessen, Giessen, Germany.
| | - Tamam Bakchoul
- Department of Transfusion Medicine, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany
| | - Jochen Wilhelm
- Department of Internal Medicine, German Center for Lung Research, Justus Liebig University, Giessen, Germany
| | - Alexander Wagner
- Department of Adult and Pediatric Cardiovascular Surgery, University Hospital Giessen, Giessen, Germany
| | - Matthias Wollbrück
- Department of Anaesthesiology and Intensive Care Medicine University Hospital Giessen, Giessen, Germany
| | - Andreas Böning
- Department of Adult and Pediatric Cardiovascular Surgery, University Hospital Giessen, Giessen, Germany
| | - Ulrich Sachs
- Institute for Clinical Immunology und Transfusion Medicine, Justus Liebig University Giessen, Giessen, Germany
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Benesch C, Heise T, Klein O, Heinemann L, Arnolds S. How to Assess the Quality of Glucose Clamps? Evaluation of Clamps Performed With ClampArt, a Novel Automated Clamp Device. J Diabetes Sci Technol 2015; 9:792-800. [PMID: 25852075 PMCID: PMC4525648 DOI: 10.1177/1932296815576957] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND There are no widely accepted parameters to assess the quality of glucose clamps. Thus, we selected different parameters describing clamp quality. These parameters were then evaluated in glucose clamps carried out with ClampArt, a novel CE-marked, state-of-the-art fully automated glucose clamp device employing continuous blood glucose (BG) measurements and minute-by-minute adaptations of glucose infusion rate (GIR). METHODS Thirty-nine glucose clamps were performed in 10 healthy and 29 subjects with type 1 diabetes (T1DM) (total duration 583 h). ClampArt-based BG measurements were compared with those obtained with a laboratory reference method. Clamp quality was assessed by 5 parameters: (1) difference (mg/dl) of all paired BG measurements of ClampArt versus reference method ("trueness"), (2) coefficient of variation (CV, %) of ClampArt's BG measurements at target clamp level ("precision"), (3) mean absolute relative difference (MARD, %) at target clamp level ("accuracy"), (4) difference (mg/dl) between ClampArt and target BG ("control deviation"), and (5) percentage operational time ("utility"). RESULTS ClampArt-based BG measurements showed a trueness of 1.2 ± 2.5 mg/dl. CV and MARD at target BG were 5.5 ± 2.1% and 5.3 ± 2.3%, respectively. There were only small deviations from target level (1.2 ± 1.6 mg/dl). Operational time was as high as 95.4% ± 4.1% (means ± SD). CONCLUSIONS The selected parameters seem to be adequate to characterize clamp quality. The novel, fully automated clamp device ClampArt achieves high clamp quality, which in future trials should be compared with other (automated and manual) clamp methods.
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Heise T, Nosek L, Klein O, Coester H, Svendsen AL, Haahr H. Insulin degludec/insulin aspart produces a dose-proportional glucose-lowering effect in subjects with type 1 diabetes mellitus. Diabetes Obes Metab 2015; 17:659-64. [PMID: 25772444 DOI: 10.1111/dom.12463] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Revised: 02/24/2015] [Accepted: 03/10/2015] [Indexed: 11/29/2022]
Abstract
AIMS To evaluate the pharmacodynamic dose-response relationship of insulin degludec/insulin aspart (IDegAsp), a novel, soluble co-formulation of the ultra-long-acting basal insulin, insulin degludec (IDeg), with the rapid-acting prandial insulin (IAsp), across different doses in patients with type 1 diabetes (T1DM). METHODS This was a randomized, single-centre, double-blind, four-period, incomplete block, crossover trial. A cohort of 33 people with T1DM received single doses (0.4, 0.6 or 0.8 U/kg) of IDegAsp or the comparator, biphasic insulin aspart 30, in a randomized sequence of four treatment periods, each separated by a washout of 13-21 days. Pharmacodynamic response was assessed using a 26-h euglycaemic glucose clamp, with blood glucose stabilized at a target of 5.5 mmol/l (100 mg/dl). RESULTS A rapid onset of action and a distinct peak attributable to IAsp was observed in the glucose infusion rate (GIR) profile, followed by a separate, flat and stable basal glucose-lowering effect attributable to the IDeg component. The mean area under the GIR curve over 24 h (AUC(GIR,0-24 h)), and the mean maximum GIR (GIR(max)) increased with increasing dose level of IDegAsp. A dose-response relationship for IDegAsp was demonstrated for AUC(GIR,0-24 h) and GIR(max), indicating dose proportionality. A dose-concentration relationship was also observed for both the basal and bolus components of IDegAsp. CONCLUSIONS IDegAsp has a clear dose-response relationship, indicating the clinical potential for straightforward titration according to individual patient needs.
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Affiliation(s)
| | | | | | | | | | - H Haahr
- Novo Nordisk A/S, Søborg, Denmark
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Heise T, Nosek L, Roepstorff C, Chenji S, Klein O, Haahr H. Distinct Prandial and Basal Glucose-Lowering Effects of Insulin Degludec/Insulin Aspart (IDegAsp) at Steady State in Subjects with Type 1 Diabetes Mellitus. Diabetes Ther 2014; 5:255-65. [PMID: 24888255 PMCID: PMC4065302 DOI: 10.1007/s13300-014-0070-2] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Indexed: 11/12/2022] Open
Abstract
INTRODUCTION/AIM Insulin degludec/insulin aspart (IDegAsp) is a soluble co-formulation of long-acting and short-acting insulin analogs. The primary objective of this study was to investigate the pharmacodynamic response of once-daily IDegAsp dosing in patients with type 1 diabetes. Pharmacokinetic response, as well as safety and tolerability, were assessed as secondary objectives. METHODOLOGY This was a single-center, open-label, single-arm study. Twenty-two subjects received once-daily insulin degludec (IDeg) (0.42 U/kg) for five consecutive days [with separate bolus insulin aspart (IAsp) as needed for safety and glycemic control], to achieve clinical steady state of the basal component. On Day 6, they received a single injection of IDegAsp (0.6 U/kg, comprising 0.42 U/kg IDeg and 0.18 U/kg IAsp). Pharmacodynamic response was assessed using a 30-h euglycemic glucose clamp, with blood glucose stabilized at a target of 5.5 mmol/L. RESULTS The glucose infusion rate profile showed a rapid onset of action and a distinct peak due to IAsp, followed by a separate, flat and stable basal glucose-lowering effect due to the IDeg component. Modeling data suggested that the pharmacodynamic profile of IDegAsp was retained with twice-daily dosing (allowing for coverage of two main meals daily). IDegAsp was well tolerated and no safety issues were identified in this trial. CONCLUSIONS In conclusion, the IAsp component of IDegAsp has a fast onset of appearance and a peak covering the prandial phase, while the IDeg component has a flat and an evenly distributed pharmacokinetic profile over 24 h. IDegAsp is the first co-formulation of a basal insulin analog with an ultra-long duration of action and a mealtime insulin analog in a single soluble injection. These properties translate into clinically relevant benefits, including improved glycemic control and reduction in hypoglycemia.
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Affiliation(s)
- Tim Heise
- Profil Institute for Metabolic Research, Hellersbergstr. 9, 41460, Neuss, Germany,
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30
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Ma Z, Parkner T, Frystyk J, Laursen T, Lauritzen T, Christiansen JS. A comparison of pharmacokinetics and pharmacodynamics of insulin aspart, biphasic insulin aspart 70, biphasic insulin aspart 50, and human insulin: a randomized, quadruple crossover study. Diabetes Technol Ther 2012; 14:589-95. [PMID: 22519735 DOI: 10.1089/dia.2011.0299] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND We compared the pharmacokinetic and pharmacodynamic profiles of insulin aspart, biphasic insulin aspart 70 (BIAsp70) and 50 (BIAsp50) (containing 70% and 50% rapid-acting insulin aspart, respectively), and soluble human insulin under experimental conditions. SUBJECTS AND METHODS In this randomized, four-period crossover study, 19 type 1 diabetes patients received subcutaneous injections of identical doses (0.2 U/kg) of insulin aspart, BIAsp70, or BIAsp50 immediately before a standardized meal or human insulin 30 min before meal. Plasma glucose and serum insulin were measured for 12 h postprandially. RESULTS The pharmacokinetic and pharmacodynamic profiles of human insulin differed from those of insulin aspart, BIAsp70, and BIAsp50. The three different aspart preparations had easily distinguishable features with regard to onset and duration of action. Insulin aspart preparations were, on average, absorbed twice as fast as human insulin. In the initial phases (0-4 h and 0-6 h), the insulin area under the concentration-time curve (AUC(ins)) was significantly higher during insulin aspart treatment compared with the others, whereas insulin aspart had a significantly lower AUC(ins) over the last 6 h (P<0.05). BIAsp70 and BIAsp50 provided insulin coverage comparable to that of human insulin over the last 6 h. Insulin aspart had the most pronounced onset of action and the shortest duration. Comparing with insulin aspart and BIAsp70, BIAsp50 revealed a closer treatment ratio to human insulin on pharmacodynamic end points. CONCLUSIONS BIAsp70 and BIAsp50 injected immediately before a meal are at least as effective as human insulin injected 30 min earlier in controlling postprandial glycemic excursions. BIAsp50 showed the greatest similarity to human insulin with regard to pharmacokinetic and pharmacodynamic profiles.
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Affiliation(s)
- Zhulin Ma
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
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31
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Nobels F, D'Hooge D, Crenier L. Switching to biphasic insulin aspart 30/50/70 from biphasic human insulin 30/50 in patients with type 2 diabetes in normal clinical practice: observational study results. Curr Med Res Opin 2012; 28:1017-26. [PMID: 22612579 DOI: 10.1185/03007995.2012.695730] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
OBJECTIVE To investigate the safety and efficacy of switching to biphasic insulin aspart (BIAsp) 30, 50 or 70 in patients with type 2 diabetes previously treated with biphasic human insulin (BHI) 30/50 (with or without oral glucose-lowering drugs) in routine clinical practice. METHODS This was a 26-week, prospective, observational study conducted in Belgium and Luxembourg. Data were collected at baseline before patients switched and at 12 and 26 weeks after starting BIAsp 30, 50 or 70. Safety endpoints were incidence and rate of hypoglycemia (major, minor, nocturnal), adverse events and body-weight changes. Efficacy assessments included HbA(1c) and 7-point self-measured plasma glucose (PG) profiles. Changes from baseline were analyzed using paired t-tests. RESULTS Of 592 patients analyzed, 72% switched to twice-daily BIAsp and 20% to three-times daily BIAsp. Upon switching, 27% of patients received intensified treatment (i.e., more daily doses than with their previous BHI). At all three data-collection points, approximately two-thirds of patients were taking BIAsp 30 and approximately one-third were taking BIAsp 50; very few patients took BIAsp 70. Mean total daily insulin dose increased significantly from baseline (51.2 U) to 26 weeks (54.3 U) and mean time of intake before meals changed from 17 minutes for BHI to ∼3 minutes with BIAsp. Incidence of hypoglycemia did not change during the study (baseline: 30.7%, week 26: 29.2%). HbA(1c) improved significantly from baseline (7.9 %) to weeks 12 and 26 (7.6% and 7.5%, respectively; p < 0.001). Mean PG profiles also showed significant improvements. As this is an observational study, some limitations should be considered such as the absence of a control group and a possible bias of increased medical attention. CONCLUSIONS Patients with long-standing type 2 diabetes can switch safely from BHI to BIAsp therapy, even if they receive intensified treatment, and they have no problems changing the timing of their insulin injections.
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Evans M, Schumm-Draeger PM, Vora J, King AB. A review of modern insulin analogue pharmacokinetic and pharmacodynamic profiles in type 2 diabetes: improvements and limitations. Diabetes Obes Metab 2011; 13:677-84. [PMID: 21410860 PMCID: PMC3380549 DOI: 10.1111/j.1463-1326.2011.01395.x] [Citation(s) in RCA: 92] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Insulin analogues have been engineered to enhance desired molecular properties without altering immunogenicity. The majority of insulin pharmacology studies are conducted in healthy volunteers and patients with type 1 diabetes. At present, there are more patients with type 2 than type 1 diabetes receiving insulin treatment. As the responsibility for initiating insulin therapy in these patients continues to shift to primary care, it will be important for general practitioners to understand the different pharmacological properties of insulin preparations in patients with type 2 diabetes, so that treatment can be adapted to meet patients' physiological and lifestyle requirements. The purpose of this review is to summarize pharmacological studies of insulin analogues in patients with type 2 diabetes. Faster onset of action of rapid acting insulin analogues has improved postprandial glycaemic control. Biphasic insulin analogues are associated with a lower incidence of nocturnal hypoglycaemia compared with human biphasic preparations and allow for intensification from once to twice or thrice daily dosing. More predictable glycaemic-lowering profiles of the insulin analogues have also led to reductions in nocturnal hypoglycaemia, particularly comparing long-acting insulin analogues with protaminated human insulin. Enhancing insulin self-association and reversible binding with albumin has led to further reductions in variability. However, improvements can still be made. Effective once daily clinical dosing of long-acting insulin analogues is not possible in all patients. In addition, the protaminated component of biphasic insulin analogues do not provide the duration of action or profile for physiological basal insulin replacement and neither insulin glargine nor insulin detemir are suitable for mixing with other insulin analogues as this would substantially alter their pharmacokinetic properties. Enhancing the pharmacological predictability and extending the duration of action could simplify insulin titration and further reduce the incidence of hypoglycaemia.
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Affiliation(s)
- M Evans
- Department of Medicine, University Hospital of Wales, Cardiff, UK.
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Brito M, Ligthelm RJ, Boemi M, Kumar A, Raz I, Koblik T, Gao Y, Christiansen JS. Intensifying existing premix therapy (BIAsp 30) with BIAsp 50 and BIAsp 70: A consensus statement. Indian J Endocrinol Metab 2011; 15:152-160. [PMID: 21897890 PMCID: PMC3156533 DOI: 10.4103/2230-8210.83396] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
In 2009, consensus guidelines were published on intensification of insulin therapy using the premix analog biphasic insulin aspart (BIAsp) 30 in the treatment of type 2 diabetes, based on the recommendations of an international, independent expert panel. The guidelines included recommendations and titration algorithms for intensification from basal insulin once (OD) or twice daily (BID) to BIAsp 30 BID, from OD BIAsp 30 to BID, and from BID BIAsp 30 to three times daily (TID). Building on these recommendations, the objective was to develop similar, simple and effective guidelines for intensification switch from a BIAsp 30 to a mid-/high-ratio premix regimen for the vast majority of patients with type 2 diabetes. A panel of independent experts with extensive clinical experience in premix analog therapy met in October 2009 to review the therapeutic role of mid- and high-ratio premixes (BIAsp 50 and 70, respectively). The panel outlined a series of algorithms for intensifying BIAsp 30 BID and TID with mid-/high-ratio premixes, along with practical suggestions relating to intensification for individual patients. A simple tool to aid dose adjustment was also developed. The guidelines suggested here should assist physicians in introducing mid-/high-ratio premixes to optimize the insulin therapy of patients with type 2 diabetes who are failing to achieve glycemic targets on a BIAsp 30 BID or TID regimen.
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Affiliation(s)
- Miguel Brito
- Department of Endocrinology and Nutrition, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | | | - Massimo Boemi
- Department of Specialist Medicine, UOC Diabetologia - INRCA-IRCCS, Ancona, Italy
| | - Ajay Kumar
- Diabetes Care and Research Centre, Patna, India
| | - Itamar Raz
- Diabetes Unit, Hadassah Ein Kerem Hospital, Jerusalem, Israel
| | - Teresa Koblik
- Cathedral and Clinic of Metabolic Diseases, Jagiellonian University, Kraków, Poland
| | - Yan Gao
- Department of Endocrinology, Peking University First Hospital, Beijing, China
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Søeborg T, Rasmussen CH, Mosekilde E, Colding-Jørgensen M. Bioavailability and variability of biphasic insulin mixtures. Eur J Pharm Sci 2011; 46:198-208. [PMID: 21703346 DOI: 10.1016/j.ejps.2011.06.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2011] [Accepted: 06/07/2011] [Indexed: 11/30/2022]
Abstract
Absorption of subcutaneously administered insulin is associated with considerable variability. Some of this variability was quantitatively explained for both soluble insulin and insulin suspensions in a recent contribution to this journal (Søeborg et al., 2009). In the present article, the absorption kinetics for mixtures of insulins is described. This requires that the bioavailability of the different insulins is considered. A short review of insulin bioavailability and a description of the subcutaneous depot thus precede the presentation of possible mechanisms associated with subcutaneous insulin degradation. Soluble insulins are assumed to be degraded enzymatically in the subcutaneous tissue. Suspended insulin crystals form condensed heaps that are assumed to be degraded from their surface by invading macrophages. It is demonstrated how the shape of the heaps affects the absorption kinetics. Variations in heap formation thus explain some of the additional variability associated with suspended insulins (e.g. NPH insulins) compared to soluble insulins. The heap model also describes how increasing concentrations of suspended insulins lead to decreasing bioavailability and lower values of Cmax. Together, the findings constitute a comprehensive, quantitative description of insulin absorption after subcutaneous administration. The model considers different concentrations and doses of soluble insulin, including rapid acting insulin analogues, insulin suspensions and biphasic insulin mixtures. The results can be used in both the development of novel insulin products and in the planning of the treatment of insulin dependent diabetic patients.
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Affiliation(s)
- Tue Søeborg
- Novo Nordisk A/S, Novo Allé, DK-2880 Bagsværd, Denmark
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35
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Kawamori R, Valensi P. IMPROVE™ observational study of biphasic insulin aspart 30/70 in patients with Type 2 diabetes mellitus. Expert Rev Endocrinol Metab 2010; 5:507-516. [PMID: 30780809 DOI: 10.1586/eem.10.31] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
The IMPROVE™ study is the largest observational study of therapy in Type 2 diabetes mellitus to date. It is a multinational study investigating the safety and efficacy of biphasic insulin aspart 30/70 (BIAsp 30) in the routine management of patients with Type 2 diabetes mellitus. Five published reports on this study have provided baseline demographic information for patients receiving BIAsp 30 in eight countries, information on the safety and efficacy outcomes for those patients and analyses of three subgroups of patients who were insulin-naive, receiving basal insulin or receiving biphasic human insulin before the start of the study. These subanalyses provided information on the optimal prescribing and dosing strategies when starting treatment with BIAsp 30 in these groups of patients in normal clinical practice. The study extends the results from clinical trials of BIAsp 30 and confirms its benefits in routine care, in a large, global, heterogeneous patient population.
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Affiliation(s)
- Ryuzo Kawamori
- a Department of Medicine, Metabolism & Endocrinology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
| | - Paul Valensi
- b Department of Endocrinology Diabetology Nutrition, Paris Nord University, AP-HP, Jean Verdier Hospital, CRNH-IdF, Bondy, France
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Christiansen JS, Liebl A, Davidson JA, Ligthelm RJ, Halimi S. Mid- and high-ratio premix insulin analogues: potential treatment options for patients with type 2 diabetes in need of greater postprandial blood glucose control. Diabetes Obes Metab 2010; 12:105-14. [PMID: 19895637 DOI: 10.1111/j.1463-1326.2009.01144.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Some patients with type 2 diabetes continue to have high postprandial blood glucose levels on twice-daily regimens of 'low-ratio' premix insulin formulations (up to 30% rapid-acting, with 70% protracted insulin). These patients require intensified insulin therapy, which can be provided by a twice- or thrice-daily regimen of mid-ratio (50% rapid-acting and 50% protaminated intermediate-acting insulin - human or analogue) or high-ratio (70% rapid-acting and 30% protaminated insulin - analogue only) premix insulin. Alternatively, a third daily injection of low-ratio premix insulin can be added to the regimen, with the option of incorporating one or more injections of mid- or high-ratio premix as required, and as an alternative to basal-bolus therapy. How these mid- and high-ratio formulations differ from the low-ratio premix insulins is reviewed here, with the aim of identifying the role of these formulations in diabetes management. Glucose clamp studies have shown that premix analogues give serum insulin levels proportional to their percentage of rapid-acting uncomplexed insulin: the higher the proportion, the greater the maximum level reached. Other pharmacokinetic parameters were not always significantly different between the mid- and high-ratio formulations. In clinical trials, postprandial plasma glucose and glycated haemoglobin A1c (HbA(1c)) levels were significantly reduced with thrice-daily mid- /high-ratio premix analogue when compared with twice-daily low-ratio biphasic human insulin (BHI) 30/70 or once-daily insulin glargine. Moreover, glycaemic control with mid-/high-ratio premix analogue was found to be similar to that with a basal-bolus therapy. Mid- and high-ratio premix regimens are generally well tolerated. The frequency of minor hypoglycaemia was reportedly higher with mid- /high-ratio premix analogues than with BHI 30, but nocturnal hypoglycaemia was less frequent. Although there is little evidence that clinical outcomes with mid-ratio premix analogues are different from those with high-ratio, they are useful additions to the low-ratio formulations for the management of diabetes, and addressing postprandial hyperglycaemia in particular.
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Affiliation(s)
- J S Christiansen
- Department of Endocrinology, Aarhus University Hospital, Aarhus, Denmark.
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Cucinotta D, Russo GT. Biphasic insulin aspart in the treatment of type 2 diabetes mellitus. Expert Opin Pharmacother 2009; 10:2905-11. [DOI: 10.1517/14656560903391714] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Abstract
MOTIVATION Most current insulin pumps include an insulin-on-board (IOB) feature to help subjects avoid problems associated with "insulin stacking." In addition, many control algorithms proposed for a closed-loop artificial pancreas make use of IOB to reduce the probability of hypoglycemic events that often occur due to the integral action of the controller. The IOB curves are generated from the pharmacodynamic (time-activity profiles) actions of subcutaneous insulin, which are obtained from glycemic clamp studies. METHODS Glycemic clamp algorithms are reviewed and in silico studies are performed to analyze the effect of glucose meter bias and noise on glycemic control and the manipulated glucose infusion rates. The glucose infusion rates are used to obtain insulin time-activity profiles, which are then used to generate IOB curves. RESULTS A model-based, three-step-ahead controller is shown to be equivalent to a proportional-integral control algorithm with time-delay compensation. A systematic glucose meter bias of +6 mg/dl results in a decrease in the glucose area under the curve of 3% but no change in the IOB profiles. CONCLUSIONS Based on these preliminary simulation studies, a substantial amount of glucose meter bias and noise during a glycemic clamp can be tolerated with little net effect on the IOB curves. It is suggested that handheld glucose meters can therefore be used in clamp studies if the measurements are filtered (averaged) before processing by the control algorithm. Clinical studies are needed to confirm these preliminary results.
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Affiliation(s)
- B Wayne Bequette
- Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, New York 12180-3590, USA.
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39
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Current literature in diabetes. Diabetes Metab Res Rev 2009; 25:i-xii. [PMID: 19405078 DOI: 10.1002/dmrr.973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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40
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Valensi P, Benroubi M, Borzi V, Gumprecht J, Kawamori R, Shaban J, Shah S, Shestakova M, Wenying Y. Initiating insulin therapy with, or switching existing insulin therapy to, biphasic insulin aspart 30/70 (NovoMix 30) in routine care: safety and effectiveness in patients with type 2 diabetes in the IMPROVE observational study. Int J Clin Pract 2009; 63:522-31. [PMID: 19187170 DOI: 10.1111/j.1742-1241.2009.02002.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
AIMS The IMPROVE observational study evaluated the safety profile and effectiveness of biphasic insulin aspart 30/70 (BIAsp 30) in patients with type 2 diabetes in routine practice in 11 countries. METHODS Patients who initiated insulin therapy with, or switched existing insulin therapy to, BIAsp 30 in routine care were eligible for this 26-week, non-interventional observational study. Data on adverse events, hypoglycaemia and glycaemic parameters were obtained from patients' diaries and medical notes. Questionnaire-based patient treatment satisfaction was also measured. We report global results and, uniquely for a diabetes observational study, country-specific data. RESULTS A total of 52,419 patients were enrolled from three prestudy treatment groups: no pharmaceutical therapy (n = 8966, diabetes duration 2.0 years, baseline HbA1c 9.9%), oral antidiabetic drugs (OADs) only (n = 33,797, diabetes duration 7.4 years, baseline HbA1c 9.2%) and insulin +/- OADs (n = 9568, diabetes duration 10.4 years, baseline HbA1c 9.3%). At final visit, HbA1c, fasting and postprandial blood glucose were significantly reduced from baseline in all subgroups (no pharmaceutical therapy: -3.1%, -5.9 and -9.0 mmol/l, respectively; OADs-only: -2.1%, -4.1 and -6.1 mmol/l; insulin +/- OADs: -2.0%, -3.3 and -5.1 mmol/l). Major hypoglycaemia rates decreased in all subgroups; minor hypoglycaemia increased in the insulin-naïve groups. There was no mean weight gain across subgroups. Across all countries, glycaemic parameters and major hypoglycaemia were reduced; weight increases were seen in some countries. Treatment satisfaction increased in all subgroups and countries following BIAsp 30 therapy. CONCLUSIONS Initiating insulin with, or switching insulin therapy to, BIAsp 30 in routine care resulted in improved glycaemic control, reduced major hypoglycaemia and greater treatment satisfaction.
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Affiliation(s)
- P Valensi
- Department of Endocrinology-Diabetology-Nutrition, Jean Verdier Hospital, AP-HP, Paris Nord University, CRNH-IdF, Bondy, France.
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