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insulin for injection (Novolin, Humulin, Lente, Semilente, Ultralente, Iletin, NPH (isophane), PZI, INS)

Tradenames: Iletin, Novolin, Humilin. Indications: - diabetes mellitus, hyperglycemia, diabetic ketoacidosis - severe hyperkalemia Contraindications: Pregnancy_category: B Safety in lactation: + Dosage: - maintenance 0.5-1 unit/kg/day (doses vary) - no maximum dose [11] - severe hyperkalemia: 5-10 units regular plus concurrent IV dextrose - profound hyperglycemia/diabetic ketoacidosis (DKA): - 0.1 units regular/kg IV bolus - infusion 100 units regular in 500 mL of normal saline (0.2 units/mL), at 0.1 units/kg/hr [allow 100 mL to drain & prime tubing prior to hook-up] 70 kg: 7 units/hr (35 mL/hr) - see insulin sliding scale - conventional SQ dosing (simple): - insulin 70/30 (70% NPH/30% regular) 2/3 in AM, 1/3 in PM - convenient inexpensive - may result in more frequent episodes of hypoglycemia & weight gain [4] - intensified SQ therapy (better but more complex) a) regular insulin 1/4 of daily dose TID before meals b) NPH or Lente 1/4 of daily dose QHS c) mealtime dosage adjusted by patient using fingerstick glucose according to algorithm d) adjustments of +/- 10% of mealtime & QHS insulin based on 3 day trends. - NPH given QHS selectively reduces fasting hypoglycemia & minimizes weight gain [4] - avoid injection of > 2.5 mL SQ at any one site [11] Injection: - 100 units/mL, 10 mL (U-100) - insulin lispro 200 units/mL (U-200) [21] - degludec 200 units/mL (U-200) - glargine 300 units/mL (U-300) - icodec (weekly, investigational) [23] - regular insulin, 500 units/mL (U-500) [21] Storage: - manufacturers recommend refrigerating unopened insulin vials & storing them at room temperature <= 45 days once opened - several types of insulin can be stored at 25 C for <= 6 months & at 37 C for <= 2 months [25] Inhalation: - dry insulin for inhalation (Exubera) [5,8]. Pharmacokinetics: Preparation Onset (hr) Peak (hr) Duration (hr) Class Lispro 15-30 min 0.5-2.5 3-6.5 rapid Aspart 10-20 min 1-3 3-5 rapid Glulisine 10-15 min 1-1.5 3-5 rapid Regular 0.5-1 2.5-5 6-8 short Semilente 1-1.5 5-10 12-16 intermediate NPH (isophane) 1-1.5 4-12 24 intermediate Lente 1-2.5 7-15 24 intermediate PZI 4-8 14-24 36 long Ultralente 4-8 10-20 24-28 long Glargine 1.1 none 24 long Detemir 3-4 6-8 12-24 long Degludec 1 12 > 40 long Icodec (weekly, investigational) [23] Novolin* 70/30 0.5-1.0 4-12 18-24 mixture Humulin* 50/50 0.5 2-5.5 18-24 mixture Novolog# 70/30 <0.5-1.0 1-4 15-18 mixture Humalog% 75/25 <0.5-1.0 1.6.5 10-16 mixture Afrezza 15 min 1 3-4 inhalation * NPH/regular; Also Humulin 70/30 # Novolog 70/30 is Aspart 30%/Aspart protamine 70% % Humalog 75/25 is Lispro 25%/Lispro protamine 75% Dosage adjustment in renal failure: creatinine clearance dose 10-50 mL/min 75% < 10 mL/min 25-50% Adverse effects: 1) not common (1-10%) - hypoglycemia*, perspiration, palpitations, tachycardia, tingling of fingers, tremors, confusion, fatigue, loss of consciousness, headache, urticaria, anaphylaxis, hypothermia, hunger, pallor, nausea, numbness of mouth, itching, redness, swelling, stinging, warmth at injection site, atrophy or hypertrophy of subcutaneous fat tissue, muscle weakness, transient presbyopia, blurred vision 2) other - transient edema [4] - insulins associated with increased risk of pancreatic cancer (RR=2.41) & liver cancer (RR=1.74) [24] - increased risk of frailty [26] - not associated with increased risk of breast cancer (RR=0.90) or prostate cancer (RR= 0.74) [24] * Caution: avoid exercise within 4 h of regular insulin * 25% of insulin errors lead to patient harm [16] * insulin is involved in ~ 1/3 of fatal medication errors [16] Drug interactions: 1) agents that increase hypoglycemic effect a) alcohol b) beta-blockers c) salicylates d) tetracycline e) alpha blockers f) MAO inhibitors 2) agents that decrease hypoglycemic effect a) corticosteroids b) oral contraceptives c) tobacco smoke d) thiazide diuretics e) thyroid hormone f) niacin g) diltiazem Mechanism of action: 1) actions via insulin protein & insulin receptor - decreases serum glucose 2) improved pancreatic islet beta cell function 3) decreased insulin resistance Notes: - average annual costs for insulin: - $231 in 2002; $736 in 2013 [19] - 1/4 of patients report insulin underuse due to high cost [20]

Interactions

molecular events drug interactions drug adverse effects of hypoglycemic agents

Related

anti-insulin antibody insulin device (device for administering insulin) insulin in serum insulin protein insulin receptor antagonist (insulin antagonist) insulin receptor; IR; (INSR) insulin resistance insulin sliding scale (ISS)

Specific

correctional insulin insulin analog (synthetic insulins, recombinant insulins)

General

parenteral hypoglycemic agent pharmaceutical insulin

Database Correlations

OMIM 176730 MORBIDMAP 176730 Entrez Gene 3630 PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  3. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  4. Medical Knowledge Self Assessment Program (MKSAP) 11, 16. 18. American College of Physicians, Philadelphia 1998, 2012, 2018
  5. Journal Watch 21(5):44, 2001 Cefalu WT et al; Inhaled Insulin Study Group. Inhaled human insulin treatment in patients with type 2 diabetes mellitus. Ann Intern Med. 2001 Feb 6;134(3):203-7. PMID: 11177333 - Nathan DM. Inhaled insulin for type 2 diabetes: solution or distraction?. Ann Intern Med. 2001 Feb 6;134(3):242-4. No abstract available. PMID: 11177338
  6. Locus Link http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=3630
  7. Insulins Prescriber's Letter 10(8):41 2004 Detail-Document#: 190806 (subscription needed) http://www.prescribersletter.com
  8. Prescriber's Letter 12(9): 2005 Diabetes Drugs on the Horizon Detail-Document#: 210905 (subscription needed) http://www.prescribersletter.com
  9. Prescriber's Letter 13(3): 2006 Detail-Document#: 220309 Comparison of Insulins (subscription needed) http://www.prescribersletter.com
  10. Prescriber's Letter 15(11): 2008 Insulin Use in Patients With Type 2 Diabetes Detail-Document#: 241120 (subscription needed) http://www.prescribersletter.com
  11. Prescriber's Letter 16(1): 2009 COMMENTARY: How Much Insulin Is Too Much? CHART: Comparison of Insulins Detail-Document#: 250107 (subscription needed) http://www.prescribersletter.com
  12. Prescriber's Letter 16(8): 2009 COMMENTARY: Is Lantus Associated With An Increased Risk of Cancer? CHART: Comparison of Insulins Detail-Document#: 250802 (subscription needed) http://www.prescribersletter.com
  13. Prescriber's Letter 16(10): 2009 CHART: How to Switch Between Insulin Products CHART: Initiation and Adjustment of Insulin Regimens for Type 2 Diabetes CHART: Comparison of Insulins Detail-Document#: 251005 (subscription needed) http://www.prescribersletter.com
  14. Testa MA et al. Comparative effectiveness of basal-bolus versus premix analog insulin on glycemic variability and patient-centered outcomes during insulin intensification in type 1 and type 2 diabetes: A randomized, controlled, crossover trial. J Clin Endocrinol Metab 2012 Oct; 97:3504. PMID: 22851487
  15. Zinman B et al. Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: A 1-year, randomized, treat-to-target trial (BEGIN Once Long). Diabetes Care 2012 Dec; 35:2464 PMID: 23043166
  16. Prescriber's Letter 21(7): 2014 Tips to Improve Insulin Safety Detail-Document#: 300713 (subscription needed) http://www.prescribersletter.com
  17. Prescriber's Letter 22(8): 2015 (subscription needed) CHART: Comparison of Insulins and Injectable Diabetes Meds CHART: Tips to Improve Insulin Safety Detail-Document#: 310825 http://www.prescribersletter.com
  18. DeWitt DE, Hirsch IB. Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: scientific review. JAMA. 2003 May 7;289(17):2254-64. Review. PMID: 12734137
  19. Hua X, Carvalho N, Tew M, Huang ES, Herman WH, Clarke P. Expenditures and Prices of Antihyperglycemic Medications in the United States: 2002-2013. JAMA. 2016 Apr 5;315(13):1400-1402. PMID: 27046369
  20. Herkert D, Vijayakumar P, Luo J et al. Cost-related insulin underuse among patients with diabetes. JAMA Intern Med 2018 Dec 3 PMID: 30508012 https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2717499
  21. Schloot NC, Hood RC, Corrigan SM, Panek RL, Heise T. Concentrated insulins in current clinical practice. Diabetes Res Clin Pract. 2019 Feb;148:93-101. PMID: 30583034 Free article. Review.
  22. NEJM Knowledge+ Endocrinology
  23. Rosenstock J, Bain SC, Gowda A et al Weekly Icodec versus Daily Glargine U100 in Type 2 Diabetes without Previous Insulin. N Engl J Med. 2023. June 24 PMID: 37356066 https://www.nejm.org/doi/full/10.1056/NEJMoa2303208 - Lingvay I, Asong M, Desouza C et al Once-Weekly Insulin Icodec vs Once-Daily Insulin Degludec in Adults With Insulin-Naive Type 2 Diabetes. The ONWARDS 3 Randomized Clinical Trial. N Engl J Med. 2023. June 24 PMID: 37354562 https://jamanetwork.com/journals/jama/fullarticle/2806635
  24. Chen Y et al Diabetes medications and cancer risk associations: a systematic review and meta-analysis of evidence over the past 10 years. Sci Rep. 2023 13(1):11844. July 22. PMID: 37481610 PMCID: PMC10363143 Free PMC article https://rdcu.be/dh4Er
  25. Harris E Insulin Maintains Activity While Stored Unrefrigerated. JAMA. Published online November 15, 2023 PMID: 37966849 https://jamanetwork.com/journals/jama/fullarticle/2812200
  26. Nishimura A et al Older Adults with Type 2 Diabetes: A Cross-Sectional Study. Drugs Aging. 2024. May 24 Not indexed in PubMed https://link.springer.com/article/10.1007/s40266-024-01119-8