Insulin- Pharmacology, Therapeutic Regimens and Principles of Intensive Insulin Therapy

Thomas Donnor, Sudipa Sarkar, Kenneth R Feingold, Bradley Anawalt, Marc R Blackman, Alison Boyce, George Chrousos, Emiliano Corpas, Wouter W de Herder, Ketan Dhatariya, Kathleen Dungan, Johannes Hofland, Sanjay Kalra, Gregory Kaltsas, Nitin Kapoor, Christian Koch, Peter Kopp, Márta Korbonits, Christopher S Kovacs, Wendy Kuohung, Blandine Laferrère, Miles Levy, Elizabeth A McGee, Robert McLachlan, Maria New, Jonathan Purnell, Rakesh Sahay, Frederick Singer, Mark A Sperling, Constantine A Stratakis, Dace L Trence, Don P Wilson, Thomas Donnor, Sudipa Sarkar, Kenneth R Feingold, Bradley Anawalt, Marc R Blackman, Alison Boyce, George Chrousos, Emiliano Corpas, Wouter W de Herder, Ketan Dhatariya, Kathleen Dungan, Johannes Hofland, Sanjay Kalra, Gregory Kaltsas, Nitin Kapoor, Christian Koch, Peter Kopp, Márta Korbonits, Christopher S Kovacs, Wendy Kuohung, Blandine Laferrère, Miles Levy, Elizabeth A McGee, Robert McLachlan, Maria New, Jonathan Purnell, Rakesh Sahay, Frederick Singer, Mark A Sperling, Constantine A Stratakis, Dace L Trence, Don P Wilson

Excerpt

Since the introduction of insulin analogs in 1996, insulin therapy options for patients with type 1 and type 2 diabetes have expanded. Insulin therapies are now able to more closely mimic physiologic insulin secretion and thus achieve better glycemic control in patients with diabetes. This chapter reviews the pharmacology of available insulins, types of insulin regimens, and principles of dosage selection and adjustment, and provides an overview of insulin pump therapy. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

Copyright © 2000-2023, MDText.com, Inc.

References

    1. Lawrence M. Landmarks in Insulin Research. Front Endocrinol. 2011;2 [Internet] [cited 2022 Nov 25] Available from.
    1. Richter B, Neises G. “Human” insulin versus animal insulin in people with diabetes mellitus. Cochrane Database Syst Rev. 2005 2005 Jan 24;(1):CD003816.
    1. FDA. 020563s115lbl.pdf [Internet]. Humalog. [cited 2022 Nov 25]. Available from:
    1. FDA. 021017s072lbl.pdf [Internet]. Humalog 75/25. [cited 2022 Nov 25]. Available from:
    1. FDA. 203314lbl.pdf [Internet]. Tresiba. [cited 2022 Nov 25]. Available from:
    1. FDA. 021172s034lbl.pdf [Internet]. NovoLog Mix 70/30. [cited 2022 Nov 25]. Available from:
    1. FDA. 021536s037lbl.pdf [Internet]. Levemir. [cited 2022 Nov 25]. Available from:
    1. FDA. 021081s072lbl.pdf [Internet]. Lantus. [cited 2022 Nov 25]. Available from:
    1. FDA. 021629s015lbl.pdf [Internet]. Apidra. [cited 2022 Nov 25]. Available from:
    1. FDA. 020986s082lbl.pdf [Internet]. Novolog. [cited 2022 Nov 25]. Available from:
    1. FDA. 21018lbl.pdf [Internet]. Humalog Mix 50/50. [cited 2022 Nov 25]. Available from:
    1. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. | Diabetes | American Diabetes Association [Internet]. [cited 2022 Nov 25]. Available from:
    1. Najjar SM, Perdomo G. Hepatic Insulin Clearance: Mechanism and Physiology. Physiology. 2019 May 1;34(3):198–215.
    1. Müssig K, Staiger H, Kantartzis K, Fritsche A, Kanz L, Häring HU. Type 2 diabetes mellitus and risk of malignancy: is there a strategy to identify a subphenotype of patients with increased susceptibility to endogenous and exogenous hyperinsulinism? Diabet Med. 2011;28(3):276–86.
    1. Karlstad Ø, Starup-Linde J, Vestergaard P, Hjellvik V. Use of Insulin and Insulin Analogs and Risk of Cancer — Systematic Review and Meta-Analysis of Observational Studies. Curr Drug Saf. 2014 Jan;8(1):333–48. T. Bazelier M, K. Schmidt M, et al.
    1. Janghorbani M, Dehghani M, Salehi-Marzijarani M. Systematic Review and Meta-analysis of Insulin Therapy and Risk of Cancer. Horm Cancer. 2012 Aug 1;3(4):137–46.
    1. Wu JW, Filion KB, Azoulay L, Doll MK, Suissa S. Effect of Long-Acting Insulin Analogs on the Risk of Cancer: A Systematic Review of Observational Studies. Diabetes Care. 2016 Jan 6;39(3):486–94.
    1. Insulin Degludec Is a New Generation Ultra-Long Acting Basal Insulin Designed To Maintain Full Metabolic Effect While Minimizing Mitogenic Potential | American Diabetes Association [Internet]. [cited 2022 Nov 27]. Available from:
    1. Schernthaner G. Immunogenicity and Allergenic Potential of Animal and Human Insulins. Diabetes Care. 1993 Dec 1;16 Supplement_3:155–65.
    1. Vardar B, Kızılcı S. Incidence of lipohypertrophy in diabetic patients and a study of influencing factors. Diabetes Res Clin Pract. 2007 Aug 1;77(2):231–6.
    1. Insulin Basics | ADA [Internet]. [cited 2022 Nov 27]. Available from:
    1. Pearson SM, Trujillo JM. Conversion from insulin glargine U-100 to insulin glargine U-300 or insulin degludec and the impact on dosage requirements. Ther Adv Endocrinol Metab. 2018 Apr 1;9(4):113–21.
    1. Pettis RJ, Muchmore D, Heinemann L. Subcutaneous Insulin Administration: Sufficient Progress or Ongoing Need? J Diabetes Sci Technol. 2019 Jan 1;13(1):3–7.
    1. Variability of Insulin Absorption and Insulin Action [Internet]. [cited 2022 Dec 17]. Available from:
    1. Gradel AKJ, Porsgaard T, Lykkesfeldt J, Seested T, Gram-Nielsen S, Kristensen NR, et al. Factors Affecting the Absorption of Subcutaneously Administered Insulin: Effect on Variability. J Diabetes Res. 2018 Jul 4;2018:1205121.
    1. Braak EWT, Woodworth JR, Bianchi R, Cerimele B, Erkelens DW, Thijssen JHH, et al. Injection Site Effects on the Pharmacokinetics and Glucodynamics of Insulin Lispro and Regular Insulin. Diabetes Care. 1996 Dec 1;19(12):1437–40.
    1. Nosek L, Coester HV, Roepstorff C, Thomsen HF, Kristensen NR, Haahr H, et al. Glucose-Lowering Effect of Insulin Degludec is Independent of Subcutaneous Injection Region. Clin Drug Investig. 2014 Sep 1;34(9):673–9.
    1. Home PD, Ashwell SG. An overview of insulin glargine. Diabetes Metab Res Rev. 2002;18(S3):S57–63.
    1. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes. N Engl J Med. 2009 Jan 8;360(2):129–39.
    1. Kennedy MSN, Masharani U. Pancreatic Hormones & Antidiabetic Drugs. In: Katzung BG, editor. Basic & Clinical Pharmacology [Internet]. 14th ed. New York, NY: McGraw-Hill Education; 2017 [cited 2022 Dec 18]. Available from:
    1. Rabkin R, Ryan MP, Duckworth WC. The renal metabolism of insulin. Diabetologia. 1984 Sep;27(3):351–7.
    1. Koda-Kimble MAnne. Applied therapeutics : the clinical use of drugs [Internet]. 9th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2009. Available from:
    1. Roach P, Woodworth JR. Clinical Pharmacokinetics and Pharmacodynamics of Insulin Lispro Mixtures. Clin Pharmacokinet. 2002 Nov 1;41(13):1043–57.
    1. Leohr J, Dellva MA, LaBell E, Coutant DE, Klein O, Plum-Moerschel L, et al. Pharmacokinetic and Glucodynamic Responses of Ultra Rapid Lispro vs Lispro Across a Clinically Relevant Range of Subcutaneous Doses in Healthy Subjects. Clin Ther. 2020 Sep 1;42(9):1762–1777.e4.
    1. Heise T, Hövelmann U, Brøndsted L, Adrian CL, Nosek L, Haahr H. Faster-acting insulin aspart: earlier onset of appearance and greater early pharmacokinetic and pharmacodynamic effects than insulin aspart. Diabetes Obes Metab. 2015 Jul;17(7):682–8.
    1. Rave K, Bott S, Heinemann L, Sha S, Becker RHA, Willavize SA, et al. Time-Action Profile of Inhaled Insulin in Comparison With Subcutaneously Injected Insulin Lispro and Regular Human Insulin. Diabetes Care. 2005 May 1;28(5):1077–82.
    1. Biester T, Kordonouri O, Danne T. Pharmacological Properties of Faster-Acting Insulin Aspart. Curr Diab Rep. 2017 Sep 23;17(11):101.
    1. Plank J, Bodenlenz M, Sinner F, Magnes C, Görzer E, Regittnig W, et al. A Double-Blind, Randomized, Dose-Response Study Investigating the Pharmacodynamic and Pharmacokinetic Properties of the Long-Acting Insulin Analog Detemir. Diabetes Care. 2005 May 1;28(5):1107–12.
    1. Lepore M, Pampanelli S, Fanelli C, Porcellati F, Bartocci L, Di Vincenzo A, et al. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes. 2000 Dec 1;49(12):2142–8.
    1. Rifkin H, Sherwin RS, Porte D, Ellenberg M, editors. Ellenberg & Rifkin’s diabetes mellitus. 5th ed. /. Stamford, Conn. : Appleton & Lange,; c1997.
    1. Lalli C, Ciofetta M, Del Sindaco P, Torlone E, Pampanelli S, Compagnucci P, et al. Long-term intensive treatment of type 1 diabetes with the short-acting insulin analog lispro in variable combination with NPH insulin at mealtime. Diabetes Care. 1999 Mar 1;22(3):468–77.
    1. Brunelle RL, Llewelyn J, Anderson JH, Jr, Gale EAM, Koivisto VA. Meta-Analysis of the Effect of Insulin Lispro on Severe Hypoglycemia in Patients With Type 1 Diabetes. Diabetes Care. 1998 Oct 1;21(10):1726–31.
    1. Pampanelli S, Torlone E, Ialli C, Sindaco PD, Ciofetta M, Lepore M, et al. Improved Postprandial Metabolic Control After Subcutaneous Injection of a Short-Acting Insulin Analog in IDDM of Short Duration With Residual Pancreatic β-Cell Function. Diabetes Care. 1995 Nov 1;18(11):1452–9.
    1. Cobry E, McFann K, Messer L, Gage V, VanderWel B, Horton L, et al. Timing of Meal Insulin Boluses to Achieve Optimal Postprandial Glycemic Control in Patients with Type 1 Diabetes. Diabetes Technol Ther. 2010 Mar;12(3):173–7.
    1. Luijf YM, Bon AC, van, Hoekstra JB, DeVries JH. Premeal Injection of Rapid-Acting Insulin Reduces Postprandial Glycemic Excursions in Type 1 Diabetes. Diabetes Care. 2010 Oct;33(10):2152.
    1. Klonoff DC, Evans ML, Lane W, Kempe HP, Renard E, DeVries JH, et al. A randomized, multicentre trial evaluating the efficacy and safety of fast-acting insulin aspart in continuous subcutaneous insulin infusion in adults with type 1 diabetes (onset 5). Diabetes Obes Metab. 2019;21(4):961–7.
    1. Warren M, Bode B, Cho JI, Liu R, Tobian J, Hardy T, et al. Improved postprandial glucose control with ultra rapid lispro versus lispro with continuous subcutaneous insulin infusion in type 1 diabetes: PRONTO-Pump-2. Diabetes Obes Metab. 2021;23(7):1552–61.
    1. Important Safety Information | Insulin Pump Therapy | Omnipod [Internet]. [cited 2023 Feb 12]. Available from:
    1. Insulin Compatibility [Internet]. Support. [cited 2023 Feb 5]. Available from:
    1. Medtronic Diabetes Useful Information [Internet]. Medtronic Diabetes. 2012 [cited 2023 Feb 12]. Available from:
    1. Tupola S, Komulainen J, Jääskeläinen J, Sipilä I. Post-prandial insulin lispro vs. human regular insulin in prepubertal children with Type 1 diabetes mellitus. Diabet Med J Br Diabet Assoc. 2001 Aug;18(8):654–8.
    1. Kumar D. Lispro Analog for Treatment of Generalized Allergy to Human Insulin. Diabetes Care. 1997 Sep 1;20(9):1357–9.
    1. Heise T, Hövelmann U, Zijlstra E, Stender-Petersen K, Jacobsen JB, Haahr H. A Comparison of Pharmacokinetic and Pharmacodynamic Properties Between Faster-Acting Insulin Aspart and Insulin Aspart in Elderly Subjects with Type 1 Diabetes Mellitus. Drugs Aging. 2017;34(1):29–38.
    1. Kildegaard J, Buckley ST, Nielsen RH, Povlsen GK, Seested T, Ribel U, et al. Elucidating the Mechanism of Absorption of Fast-Acting Insulin Aspart: The Role of Niacinamide. Pharm Res. 2019;36(3):49.
    1. Rave K, Heise T, Heinemann L, Boss AH. Inhaled Technosphere® Insulin in Comparison to Subcutaneous Regular Human Insulin: Time Action Profile and Variability in Subjects with Type 2 Diabetes. J Diabetes Sci Technol. 2008 Mar;2(2):205.
    1. Coverage of Postprandial Blood Glucose Excursions With Inhaled Technosphere Insulin in Comparison to Subcutaneously Injected Regular Human Insulin in Subjects With Type 2 Diabetes | Diabetes Care | American Diabetes Association [Internet]. [cited 2022 Dec 28]. Available from:
    1. Rosenstock J, Bergenstal R, DeFronzo RA, Hirsch IB, Klonoff D, Boss AH, et al. Efficacy and Safety of Technosphere Inhaled Insulin Compared With Technosphere Powder Placebo in Insulin-Naive Type 2 Diabetes Suboptimally Controlled With Oral Agents. Diabetes Care. 2008 Nov 1;31(11):2177–82.
    1. Rosenstock J, Lorber DL, Gnudi L, Howard CP, Bilheimer DW, Chang PC, et al. Prandial inhaled insulin plus basal insulin glargine versus twice daily biaspart insulin for type 2 diabetes: a multicentre randomised trial. The Lancet. 2010 Jun 26;375(9733):2244–53.
    1. AFREZZA® (insulin human) Inhalation Powder.
    1. The pharmacokinetics and pharmacodynamics of rapid‐acting insulin analogues and their clinical consequences - Home - 2012 - Diabetes, Obesity and Metabolism - Wiley Online Library [Internet]. [cited 2022 Dec 28]. Available from:
    1. T H, K SP, U H, Jb J, L N, E Z, et al. Pharmacokinetic and Pharmacodynamic Properties of Faster-Acting Insulin Aspart versus Insulin Aspart Across a Clinically Relevant Dose Range in Subjects with Type 1 Diabetes Mellitus. Clin Pharmacokinet [Internet]. 2017 Jun [cited 2022 Dec 28];56(6). Available from:
    1. Heise T, Linnebjerg H, Coutant D, LaBell E, Zijlstra E, Kapitza C, et al. Ultra rapid lispro lowers postprandial glucose and more closely matches normal physiological glucose response compared to other rapid insulin analogues: A phase 1 randomized, crossover study. Diabetes Obes Metab. 2020;22(10):1789–98.
    1. Bolli GB, Owens DR. Insulin glargine. Lancet Lond Engl. 2000 Aug 5;356(9228):443–5.
    1. Heinemann L, Linkeschova R, Rave K, Hompesch B, Sedlak M, Heise T. Time-action profile of the long-acting insulin analog insulin glargine (HOE901) in comparison with those of NPH insulin and placebo. Diabetes Care. 2000 May 1;23(5):644–9.
    1. Mudaliar S, Mohideen P, Deutsch R, Ciaraldi TP, Armstrong D, Kim B, et al. Intravenous Glargine and Regular Insulin Have Similar Effects on Endogenous Glucose Output and Peripheral Activation/Deactivation Kinetic Profiles. Diabetes Care. 2002 Sep 1;25(9):1597–602.
    1. Yki-Järvinen H, Dressler A, Ziemen M. HOE 901/300s Study Group. Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. HOE 901/3002 Study Group. Diabetes Care. 2000 Aug 1;23(8):1130–6.
    1. Ratner RE, Hirsch IB, Neifing JL, Garg SK, Mecca TE, Wilson CA. Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes. U.S. Study Group of Insulin Glargine in Type 1 Diabetes. Diabetes Care. 2000 May 1;23(5):639–43.
    1. Heise T, Hermanski L, Nosek L, Feldman A, Rasmussen S, Haahr H. Insulin degludec: four times lower pharmacodynamic variability than insulin glargine under steady-state conditions in type 1 diabetes. Diabetes Obes Metab. 2012;14(9):859–64.
    1. Ratner RE, Gough SCL, Mathieu C, Prato SD, Bode B, Mersebach H, et al. Hypoglycaemia risk with insulin degludec compared with insulin glargine in type 2 and type 1 diabetes: a pre-planned meta-analysis of phase 3 trials. Diabetes Obes Metab. 2013 Feb;15(2):175.
    1. Marso SP, McGuire DK, Zinman B, Poulter NR, Emerson SS, Pieber TR, et al. Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes. N Engl J Med. 2017 Aug 24;377(8):723–32.
    1. Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 1 Diabetes: The SWITCH 1 Randomized Clinical Trial | Clinical Pharmacy and Pharmacology | JAMA | JAMA Network [Internet]. [cited 2022 Dec 28]. Available from:
    1. Wysham C, Bhargava A, Chaykin L, de la Rosa R, Handelsman Y, Troelsen LN, et al. Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 2 Diabetes: The SWITCH 2 Randomized Clinical Trial. JAMA. 2017 Jul 4;318(1):45–56.
    1. Grunberger G. Insulin Analogs—Are They Worth It? Yes! Diabetes Care. 2014 May 10;37(6):1767–70.
    1. Riddle MC, Rosenstock J, Gerich J, Insulin Glargine 4002 Study Investigators The Treat-to-Target Trial: Randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003 Nov 1;26(11):3080–6.
    1. Vague P, Selam JL, Skeie S, De Leeuw I, Elte JWF, Haahr H, et al. Insulin Detemir Is Associated With More Predictable Glycemic Control and Reduced Risk of Hypoglycemia Than NPH Insulin in Patients With Type 1 Diabetes on a Basal-Bolus Regimen With Premeal Insulin Aspart. Diabetes Care. 2003 Mar 1;26(3):590–6.
    1. Riddle MC, Bolli GB, Ziemen M, Muehlen-Bartmer I, Bizet F, Home PD, et al. New Insulin Glargine 300 Units/mL Versus Glargine 100 Units/mL in People With Type 2 Diabetes Using Basal and Mealtime Insulin: Glucose Control and Hypoglycemia in a 6-Month Randomized Controlled Trial (EDITION 1). Diabetes Care. 2014 Sep 10;37(10):2755–62.
    1. Yki-Järvinen H, Bergenstal R, Ziemen M, Wardecki M, Muehlen-Bartmer I, Boelle E, et al. New Insulin Glargine 300 Units/mL Versus Glargine 100 Units/mL in People With Type 2 Diabetes Using Oral Agents and Basal Insulin: Glucose Control and Hypoglycemia in a 6-Month Randomized Controlled Trial (EDITION 2). Diabetes Care. 2014 Nov 8;37(12):3235–43.
    1. Bolli GB, Riddle MC, Bergenstal RM, Ziemen M, Sestakauskas K, Goyeau H, et al. New insulin glargine 300 U/ml compared with glargine 100 U/ml in insulin-naïve people with type 2 diabetes on oral glucose-lowering drugs: a randomized controlled trial (EDITION 3). Diabetes Obes Metab. 2015;17(4):386–94.
    1. Holman RR, Farmer AJ, Davies MJ, Levy JC, Darbyshire JL, Keenan JF, et al. Three-Year Efficacy of Complex Insulin Regimens in Type 2 Diabetes. N Engl J Med. 2009 Oct 29;361(18):1736–47.
    1. Basaglar Newsome C. Clin Diabetes Publ Am Diabetes Assoc. 2017 Jul;35(3):181.
    1. Commissioner O of the. FDA approves Admelog, the first short-acting “follow-on” insulin product to treat diabetes [Internet]. FDA. FDA; 2020 [cited 2022 Dec 27]. Available from:
    1. Sun B, Sengupta N, Rao A, Donnelly C, Waichale V, Roy AS, et al. Similar immunogenicity profiles between the proposed biosimilar MYL-1501D and reference insulin glargine in patients with diabetes mellitus: the phase 3 INSTRIDE 1 and INSTRIDE 2 studies. BMC Endocr Disord. 2021 Jun 26;21(1):129.
    1. Blevins TC, Barve A, Sun B, Raiter Y, Aubonnet P, Muniz R, et al. Efficacy and safety of MYL-1501D versus insulin glargine in patients with type 2 diabetes after 24 weeks: Results of the phase III INSTRIDE 2 study. Diabetes Obes Metab. 2019;21(1):129–35.
    1. Blevins TC, Barve A, Raiter Y, Aubonnet P, Athalye S, Sun B, et al. Efficacy and safety of MYL-1501D versus insulin glargine in people with type 1 diabetes mellitus: Results of the INSTRIDE 3 phase 3 switch study. Diabetes Obes Metab. 2020;22(3):365–72.
    1. Cryer PE. Mechanisms of Hypoglycemia-Associated Autonomic Failure in Diabetes. N Engl J Med. 2013 Jul 25;369(4):362–72.
    1. The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus N Engl J Med. 1993 Sep 30;329(14):977–86.
    1. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). The Lancet. 1998 Sep 12;352(9131):837–53.
    1. Effects of Intensive Glucose Lowering in Type 2 Diabetes | NEJM [Internet]. [cited 2022 Dec 25]. Available from:
    1. Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2008 Jun 12;358(24):2560–72.
    1. Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society. Diabetes Care. 2013 Apr 13;36(5):1384–95.
    1. McCoy RG, Lipska KJ, Yao X, Ross JS, Montori VM, Shah ND. Intensive Treatment and Severe Hypoglycemia Among Adults With Type 2 Diabetes. JAMA Intern Med. 2016 Jul 1;176(7):969–78.
    1. Desouza C, Salazar H, Cheong B, Murgo J, Fonseca V. Association of Hypoglycemia and Cardiac Ischemia: A study based on continuous monitoring. Diabetes Care. 2003 May 1;26(5):1485–9.
    1. Frier BM, Schernthaner G, Heller SR. Hypoglycemia and Cardiovascular Risks. Diabetes Care. 2011 May;34 Suppl 2:S132–7.
    1. Donner T, Muñoz M. Update on Insulin Therapy for Type 2 Diabetes. J Clin Endocrinol Metab. 2012 May 1;97(5):1405–13.
    1. Miller ME, Bonds DE, Gerstein HC, Seaquist ER, Bergenstal RM, Calles-Escandon J, et al. The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study. BMJ. 2010 Jan 8;340:b5444.
    1. Bremer JP, Jauch-Chara K, Hallschmid M, Schmid S, Schultes B. Hypoglycemia Unawareness in Older Compared With Middle-Aged Patients With Type 2 Diabetes. Diabetes Care. 2009 Aug;32(8):1513–7.
    1. de Galan BE, Zoungas S, Chalmers J, Anderson C, Dufouil C, Pillai A, et al. Cognitive function and risks of cardiovascular disease and hypoglycaemia in patients with type 2 diabetes: the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Diabetologia. 2009 Nov 1;52(11):2328–36.
    1. ElSayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, et al. 6. Glycemic Targets: Standards of Care in Diabetes—2023. Diabetes Care. 2022 Dec 12;46 Supplement_1:S97–110.
    1. Laffel LM, Kanapka LG, Beck RW, Bergamo K, Clements MA, Criego A, et al. Effect of Continuous Glucose Monitoring on Glycemic Control in Adolescents and Young Adults With Type 1 Diabetes. JAMA. 2020 Jun 16;323(23):2388–96.
    1. Pratley RE, Kanapka LG, Rickels MR, Ahmann A, Aleppo G, Beck R, et al. Effect of Continuous Glucose Monitoring on Hypoglycemia in Older Adults With Type 1 Diabetes. JAMA. 2020 Jun 16;323(23):2397–406.
    1. Meneghini L, Atkin SL, Gough SCL, Raz I, Blonde L, Shestakova M, et al. The Efficacy and Safety of Insulin Degludec Given in Variable Once-Daily Dosing Intervals Compared With Insulin Glargine and Insulin Degludec Dosed at the Same Time Daily: A 26-week, randomized, open-label, parallel-group, treat-to-target trial in individuals with type 2 diabetes. Diabetes Care. 2013 Mar 14;36(4):858–64.
    1. Rosenstock J, Davies M, Home PD, Larsen J, Koenen C, Schernthaner G. A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia. 2008 Mar;51(3):408–16.
    1. Davies MJ, Derezinski T, Pedersen CB, Clauson P. Reduced Weight Gain with Insulin Detemir Compared to NPH Insulin Is Not Explained by a Reduction in Hypoglycemia. Diabetes Technol Ther. 2008 Aug;10(4):273–7.
    1. Buse JB, Wolffenbuttel BHR, Herman WH, Hippler S, Martin SA, Jiang HH, et al. The DURAbility of Basal versus Lispro mix 75/25 insulin Efficacy (DURABLE) Trial. Diabetes Care. 2011 Feb;34(2):249–55.
    1. Radermecker RP, Scheen AJ. Allergy reactions to insulin: effects of continuous subcutaneous insulin infusion and insulin analogues. Diabetes Metab Res Rev. 2007;23(5):348–55.
    1. Babiker A, Datta V. Lipoatrophy with insulin analogues in type I diabetes. Arch Dis Child. 2011 Jan 1;96(1):101–2.
    1. Colhoun HM. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia. 2009 Sep;52(9):1755–65.
    1. Jonasson JM, Ljung R, Talbäck M, Haglund B, Gudbjörnsdòttir S, Steineck G. Insulin glargine use and short-term incidence of malignancies—a population-based follow-up study in Sweden. Diabetologia. 2009 Sep 1;52(9):1745–54.
    1. Hemkens LG, Grouven U, Bender R, Günster C, Gutschmidt S, Selke GW, et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia. 2009 Sep;52(9):1732–44.
    1. Home PD, Lagarenne P. Combined randomised controlled trial experience of malignancies in studies using insulin glargine. Diabetologia. 2009;52(12):2499–506.
    1. Basal Insulin and Cardiovascular and Other Outcomes in Dysglycemia | NEJM [Internet]. [cited 2022 Dec 25]. Available from:
    1. Schroeder EB, Neugebauer R, Reynolds K, Schmittdiel JA, Loes L, Dyer W, et al. Association of Cardiovascular Outcomes and Mortality With Sustained Long-Acting Insulin Only vs Long-Acting Plus Short-Acting Insulin Treatment. JAMA Netw Open. 2021 Sep 24;4(9):e2126605.
    1. Hirsch IB. Type 1 Diabetes Mellitus and the Use of Flexible Insulin Regimens. Am Fam Physician. 1999 Nov 15;60(8):2343–52.
    1. Low Wang CC, Shah AC. Medical Management of Type 1 Diabetes [Internet]. American Diabetes Association; 2017 [cited 2022 Dec 19]. Available from:
    1. Chiang JL, Kirkman MS, Laffel LMB, Peters AL. on behalf of the Type 1 Diabetes Sourcebook Authors. Type 1 Diabetes Through the Life Span: A Position Statement of the American Diabetes Association. Diabetes Care. 2014 Jun 12;37(7):2034–54.
    1. Intensive Diabetes Treatment and Cardiovascular Disease in Patients with Type 1 Diabetes. N Engl J Med. 2005 Dec 22;353(25):2643–53.
    1. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009 Jan 1;32(1):193–203.
    1. Hermann LS. Optimising Therapy for Insulin-Treated Type 2 Diabetes Mellitus. Drugs Aging. 2000 Oct 1;17(4):283–94.
    1. DeWitt DE, Dugdale DC. Using New Insulin Strategies in the Outpatient Treatment of DiabetesClinical Applications. JAMA. 2003 May 7;289(17):2265–9.
    1. Fanelli CG, Pampanelli S, Porcellati F, Rossetti P, Brunetti P, Bolli GB. Administration of Neutral Protamine Hagedorn Insulin at Bedtime versus with Dinner in Type 1 Diabetes Mellitus To Avoid Nocturnal Hypoglycemia and Improve Control. Ann Intern Med. 2002 Apr 2;136(7):504–14.
    1. Francis AJ, Home PD, Hanning I, Alberti KG, Tunbridge WM. Intermediate acting insulin given at bedtime: effect on blood glucose concentrations before and after breakfast. Br Med J Clin Res Ed. 1983 Apr 9;286(6372):1173–6.
    1. Raskin P, Bode BW, Marks JB, Hirsch IB, Weinstein RL, McGill JB, et al. Continuous Subcutaneous Insulin Infusion and Multiple Daily Injection Therapy Are Equally Effective in Type 2 Diabetes : A randomized, parallel-group, 24-week study. Diabetes Care. 2003 Sep 1;26(9):2598–603.
    1. Mudaliar S, Edelman SV. INSULIN THERAPY IN TYPE 2 DIABETES. Endocrinol Metab Clin North Am. 2001 Dec 1;30(4):935–82.
    1. Bode BW, Sabbah HT, Gross TM, Fredrickson LP, Davidson PC. Diabetes management in the new millennium using insulin pump therapy. Diabetes Metab Res Rev. 2002;18(S1):S14–20.
    1. Bode BW, Tamborlane WV, Davidson PC. Insulin pump therapy in the 21st century: Strategies for successful use in adults, adolescents, and children with diabetes. Postgrad Med. 2002 May;111(5):69–77.
    1. Pickup J, Keen H. Continuous Subcutaneous Insulin Infusion at 25 Years: Evidence base for the expanding use of insulin pump therapy in type 1 diabetes. Diabetes Care. 2002 Mar 1;25(3):593–8.
    1. Brown SA, Kovatchev BP, Raghinaru D, Lum JW, Buckingham BA, Kudva YC, et al. Six-Month Randomized, Multicenter Trial of Closed-Loop Control in Type 1 Diabetes. N Engl J Med. 2019 Oct 31;381(18):1707–17.
    1. Weaver KW, Hirsch IB. The Hybrid Closed-Loop System: Evolution and Practical Applications. Diabetes Technol Ther. 2018 Jun;20(S2):S2–16.
    1. Breton MD, Kovatchev BP. One Year Real-World Use of the Control-IQ Advanced Hybrid Closed-Loop Technology. Diabetes Technol Ther. 2021 Sep;23(9):601–8.
    1. Berget C, Sherr JL, DeSalvo DJ, Kingman RS, Stone SL, Brown SA, et al. Clinical Implementation of the Omnipod 5 Automated Insulin Delivery System: Key Considerations for Training and Onboarding People With Diabetes. Clin Diabetes. 2022 Apr 15;40(2):168–84.
    1. Zhou K, Isaacs D. Closed-Loop Artificial Pancreas Therapy for Type 1 Diabetes. Curr Cardiol Rep. 2022 Sep 1;24(9):1159–67.
    1. Blonde L, Merilainen M, Karwe V, Raskin P, Group TS. Patient-directed titration for achieving glycaemic goals using a once-daily basal insulin analogue: an assessment of two different fasting plasma glucose targets - the TITRATETM study. Diabetes Obes Metab. 2009;11(6):623–31.
    1. Holleman F, Van Den Brand JJ, Hoven RA, Van Der Linden JM, Van Der Tweel I, Hoekstra JBL, et al. Comparison of LysB28, ProB29-Human Insulin Analog and Regular Human Insulin in the Correction of Incidental Hyperglycemia. Diabetes Care. 1996 Dec 1;19(12):1426–9.
    1. Kong N, Kitchen MM, Ryder RE. The use of lispro for high sugar content snacks between meals in intensive insulin regimens. Diabet Med J Br Diabet Assoc. 2000 Apr;17(4):331–2.
    1. Training in flexible, intensive insulin management to enable dietary freedom in people with type 1 diabetes: dose adjustment for normal eating (DAFNE) randomised controlled trial. BMJ. 2002 Oct 5;325(7367):746.
    1. Hirsch IB, Farkas-Hirsch R, Skyler JS. Intensive Insulin Therapy for Treatment of Type I Diabetes. Diabetes Care. 1990 Dec 1;13(12):1265–83.
    1. Riddell MC, Gallen IW, Smart CE, Taplin CE, Adolfsson P, Lumb AN, et al. Exercise management in type 1 diabetes: a consensus statement. Lancet Diabetes Endocrinol. 2017 May 1;5(5):377–90.
    1. Moser O, Riddell MC, Eckstein ML, Adolfsson P, Rabasa-Lhoret R, van den Boom L, et al. Glucose management for exercise using continuous glucose monitoring (CGM) and intermittently scanned CGM (isCGM) systems in type 1 diabetes: position statement of the European Association for the Study of Diabetes (EASD) and of the International Society for Pediatric and Adolescent Diabetes (ISPAD) endorsed by JDRF and supported by the American Diabetes Association (ADA). Diabetologia. 2020 Dec 1;63(12):2501–20.
    1. Evidence of a Strong Association Between Frequency of Self-Monitoring of Blood Glucose and Hemoglobin A1c Levels in T1D Exchange Clinic Registry Participants | Diabetes Care | American Diabetes Association [Internet]. [cited 2022 Dec 18]. Available from:
    1. Can capillary whole blood glucose and venous plasma glucose measurements be used interchangeably in diagnosis of diabetes mellitus? [Internet]. [cited 2022 Dec 18]. Available from:
    1. Danne T, Nimri R, Battelino T, Bergenstal RM, Close KL, DeVries JH, et al. International Consensus on Use of Continuous Glucose Monitoring. Diabetes Care. 2017 Nov 10;40(12):1631–40.
    1. Haak T, Hanaire H, Ajjan R, Hermanns N, Riveline JP, Rayman G. Flash Glucose-Sensing Technology as a Replacement for Blood Glucose Monitoring for the Management of Insulin-Treated Type 2 Diabetes: a Multicenter, Open-Label Randomized Controlled Trial. Diabetes Ther. 2017 Feb;8(1):55–73.
    1. Bolinder J, Antuna R, Geelhoed-Duijvestijn P, Kröger J, Weitgasser R. Novel glucose-sensing technology and hypoglycaemia in type 1 diabetes: a multicentre, non-masked, randomised controlled trial. The Lancet. 2016 Nov 5;388(10057):2254–63.
    1. Continuous glucose monitoring in people with diabetes: the randomized controlled Glucose Level Awareness in Diabetes Study (GLADIS) - New - 2015 - Diabetic Medicine - Wiley Online Library [Internet]. [cited 2022 Dec 18]. Available from:
    1. Glycaemic control in type 1 diabetes during real time continuous glucose monitoring compared with self monitoring of blood glucose: meta-analysis of randomised controlled trials using individual patient data | The BMJ [Internet]. [cited 2022 Dec 18]. Available from:
    1. Managing Sick Days | Diabetes | CDC [Internet]. 2022 [cited 2022 Dec 18]. Available from:

Source: PubMed

3
Tilaa