Continuing Education Activity

NPH (neutral protamine Hagedorn) insulin is a medication used to treat and manage diabetes mellitus, which is a significant risk factor for coronary artery disease. Most cases are not attributable to any specific etiology. This activity reviews the indications, contraindications, activity, adverse events, and other key elements of NPH insulin therapy in the clinical setting as relates to the essential points needed by members of an interprofessional team managing the care of patients with diabetes mellitus and its related conditions and sequelae.

Objectives:

• Describe the mechanism of action of NPH insulin.
• Summarize the adverse effects and contraindications of NPH insulin.
• Describe appropriate monitoring and toxicity of NPH insulin.
• Outline and explain interprofessional team strategies for improving care coordination and communication to advance NPH insulin and improve outcomes.

Indications

NPH (Neutral Protamine Hagedorn) insulin is an insoluble intermediate-acting insulin preparation first created in 1946. The name refers to N for neutral, P for protamine (a protein), and H for its creator scientist name Hans Christian Hagedorn. It is on the list of essential medicines of the World Health Organization (WHO). NPH insulin is FDA-approved in the adult and pediatric population to control type 1 and type 2 diabetes mellitus. It is currently the most widely used basal insulin that simulates the physiological basal insulin action. Basal insulin provides a constant supply of insulin in the body necessary for glucose regulation despite fasting, such as between meals and overnight. NPH insulin offers a sustained release of insulin over an extended period.[1][2][3][4] It is also useful in gestational diabetes. Pregnancy may require higher doses of insulin.

American Diabetes Association guidelines recommend an NPH insulin dose of 0.4 to 1.0 units/kg/day subcutaneously to manage type 1 diabetes mellitus. A higher dose is necessary during medical illness and puberty. A dose of 0.1 to 0.2 units/kg/day subcutaneously is recommended in type 2 diabetes mellitus depending on body weight and the patient’s hyperglycemia. The treatment is individualized, and the NPH insulin dose is titrated accordingly over days to weeks.[5]

Mechanism of Action

NPH insulin is an isophane suspension of human insulin and is categorized as an intermediate-acting insulin. It helps increase the cellular intake of glucose in the liver, adipose tissue, and skeletal muscles. It acts as basal insulin and stimulates the liver to promote hepatic glycogen synthesis, fatty acid metabolism for lipoprotein synthesis. In skeletal muscles, it promotes glycogen and protein synthesis. In adipose tissue, it helps in triglyceride synthesis and regulates lipolysis by inhibiting triglyceride hydrolysis. At the cellular level, it makes the cell membrane permeable for ions such as potassium, magnesium, and phosphorus and increases their cellular uptake.  

The intermediate-acting NPH insulin is obtained from the precipitation of recombinant synthesized human insulin with zinc in the presence of protamine, a basic polyarginine peptide. This process occurs at a neutral pH in an insulin and protamine ratio of 5: 1. This formulation method gives NPH the property of protraction, i.e., slow release of insulin from the precipitated insulin present at the injection site after subcutaneous injection.[1][2][3][4][5] After injecting the protein-insulin complex, the solvent from NPH insulin suspension diffuses into the subcutaneous tissue. These insulin crystals are stacked up like a heap at the injection depot and dissolve gradually, leading to the protracted action of NPH.

Later protamine-splitting enzymes and macrophages invade the subcutaneous tissue and dissolve the NPH insulin suspension heaps, thus releasing insulin. These varied heaps are also thought to be the cause of variability present in the pharmacodynamics and pharmacokinetics of NPH insulin. The exact mechanism of binding of preformed insulin-protamine aggregate and NPH insulin dissociation at tissue level is unknown.[1][3][5]

Pharmacodynamics and Pharmacokinetics

• The onset of action - 1 to 3 hours
• Time to Peak effect - 4 to 8 hours
• Time to reach peak effect in plasma – 6 to 10 hours
• Total duration - 14 to 24 hours       
• Distribution – Fast distribution in extracellular fluid
• Metabolism – Mainly liver. Some metabolism in kidney and muscle.
• Excretion – Urine metabolites

Administration

Crystalline NPH insulin administration is subcutaneous, not intramuscular or intravenous. NPH insulin is available in a two-phase solution, which means that apart from NPH, it has a solvent or a rapid-acting insulin solution. It comes in the form of a subcutaneous suspension or suspension pen-injector. Refer to the label of a specific product for more details regarding formulations and dose concentrations.  

The abdominal subcutaneous injection causes quicker absorption as compared to arms or thighs. The most significant advantage of NPH is that it can be included in premixed formulation with regular insulin. NPH in premixed formulations does not affect the potency and time-action profile of regular insulin. Exercise, massage, and local heat application increase NPH insulin absorption.[1][4][6]

NPH insulin pen requires adequate mixing to get complete resuspension before injecting it. It may be given once or twice daily.[7][8] Since the action profile of NPH insulin does not cover 24 hours, a twice-daily dose in the morning and evening or bedtime is the recommended regimen, which applies to the premixed formulations as well. Premixed formulations contain 70 to 75% of NPH insulin. The American Diabetes Association recommends moving to premixed formulations in well-controlled diabetes mellitus when HbA1c remains above target, the basal insulin is well titrated, or if the dose exceeds 0.5 units/kg/day.[9][6]

Adverse Effects

NPH insulin has a somewhat higher risk of hypoglycemia. Inadequate resuspension is thought to contribute to the high day-to-day variability in the pharmacodynamic and pharmacokinetic profile of NPH insulin, leading to hypoglycemia. Patients can adequately resuspend NPH by rotating the vial several times until it is uniformly cloudy[1][5][3][6]

It is often difficult to obtain the target glycosylated hemoglobin A1c due to its variable absorption and rapid peak.[10] Also, breakfast injection may not provide coverage till the evening dose, and likewise, the evening dose may not meet the insulin requirement until morning.

Nocturnal hypoglycemia: The patient is given NPH insulin in the evening. NPH Insulin peak occurs at midnight when the body does not require as much insulin and may cause nocturnal hypoglycemia.

Fasting hyperglycemia: Morning blood glucose can be high in patients who take NPH insulin in the evening. The duration of insulin action is not for its effect to last until the morning, potentially leading to fasting hyperglycemia, managed by giving NPH insulin at bedtime rather than with the evening meal. Fasting hyperglycemia can also occur with the dawn phenomenon, where insulin resistance and higher insulin need occurs after 5:00 AM.[4]

NPH insulin can cause weight gain.[11] Other side effects include peripheral edema, hypokalemia, and lipodystrophy, which may manifest as skin atrophy or hypertrophy.

Hypersensitivity reaction to insulin usually includes a local injection site reaction such as swelling or redness, but rarely life-threatening anaphylaxis can also occur.[12][13]

Contraindications

NPH insulin is contraindicated in hypersensitivity reactions. Patients may become hypersensitive to insulin formulation or any of the drug products. Allergic reactions to various allergens or additives such as zinc, protamine, and metal-cresol can occur. The patient may have pruritis, followed by erythema and rash all over the body.[14] NPH insulin is also contraindicated in patients who have repeated episodes of severe hypoglycemia. Hypoglycemia can be life-threatening.

Monitoring

NPH cannot classify as ideal basal insulin. It shows much variability in its absorption and action after subcutaneous injection.[1][3] This situation leads to fluctuations in blood glucose control and causes hypoglycemic episodes. For this reason, it requires meticulous monitoring, including fasting blood glucose and changes in HbA1c values.[7][11] NPH insulin requires electrolyte monitoring due to the risk of hypokalemia. In addition to consistent glucose monitoring, it requires monitoring the patient's physical activity because it may change the insulin requirement. Likewise, diet patterns require vigilance.

Frequent glucose monitoring is required in children on NPH insulin because of the greatly varying dose need and marked changes in insulin requirements during the growth period of children.[6]

Toxicity

NPH insulin toxicity can lead to severe hypoglycemia, which can cause seizures and even irreversible neurological deficits. It may be life-threatening or also cause death. Patients with renal or hepatic impairment are at higher risk of having hypoglycemia. Iatrogenic hypoglycemia can occur in medical facilities. Mild/moderate hypoglycemia is manageable by taking sugar-containing food or drinks. Diabetes mellitus patients and those on NPH insulin should have a source of sugar with them. Severe hypoglycemia and unconscious patients require hospitalization. Patients require treatment with an injection of glucagon or intravenous administration of glucose.

Enhancing Healthcare Team Outcomes

For a patient to achieve successful treatment with NPH insulin, an interprofessional team effort is necessary. Patient education is imperative to improve outcomes from NPH insulin treatment. Healthcare workers should teach patients how to resuspend NPH premixed insulin before injection. Health care professionals, particularly the diabetes nurse educator, should demonstrate the correct injection technique and educate patients about the importance of timing and accuracy of dosage. Regular monitoring is vital to avoid adverse effects. Patients need a detailed explanation of the side effects of insulin, and if available, a dedicated diabetic education session by a certified diabetic educator is necessary; this can be a nurse or pharmacist, preferably with specialty training in diabetes management. This interprofessional approach will drive improved patient compliance and outcomes with fewer adverse effects. [Level 5]

Patients may reduce insulin dose or miss it altogether, either because of the fear of hypoglycemia or the high cost of insulin. The high price is also a barrier to compliance. Some patients may find inflexible dose timing problematic due to social factors and work schedules. NPH insulin time-specific dosing schedule may require a lifestyle change, which may impact adherence to therapy. An interprofessional approach should be adopted, including a dietician, nurses, and primary care physician to improve outcomes. An endocrinology specialist should be involved in caring for patients with difficult to control diabetes mellitus or patients with labile blood glucose. An interprofessional approach, including clinicians, nurses, pharmacists, and dieticians, can improve the odds of successful glucose control with NPH insulin. [Level 5]

Recent clinical trials have shown that modern basal insulin analogs such as insulin glargine and insulin detemir have a lower risk of hypoglycemia and lower variability of fasting blood glucose compared to NPH insulin. But in clinical practice, these new analogs may not have better outcomes regarding the quality of life, morbidity, or cost.[10][2][6]

Review Questions

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References

1.

Lucidi P, Porcellati F, Marinelli Andreoli A, Carriero I, Candeloro P, Cioli P, Bolli GB, Fanelli CG. Pharmacokinetics and Pharmacodynamics of NPH Insulin in Type 1 Diabetes: The Importance of Appropriate Resuspension Before Subcutaneous Injection. Diabetes Care. 2015 Dec;38(12):2204-10. [PubMed: 26358287]

2.

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;23(5):644-9. [PubMed: 10834424]

3.

Singh AK, Gangopadhyay KK. Modern basal insulin analogs: An incomplete story. Indian J Endocrinol Metab. 2014 Nov;18(6):784-93. [PMC free article: PMC4192982] [PubMed: 25364672]

4.

Hirsch IB. Type 1 diabetes mellitus and the use of flexible insulin regimens. Am Fam Physician. 1999 Nov 15;60(8):2343-52, 2355-6. [PubMed: 10593324]

5.

Heise T, Mathieu C. Impact of the mode of protraction of basal insulin therapies on their pharmacokinetic and pharmacodynamic properties and resulting clinical outcomes. Diabetes Obes Metab. 2017 Jan;19(1):3-12. [PMC free article: PMC5215074] [PubMed: 27593206]

6.

Landgraf W, Sandow J. Recombinant Human Insulins - Clinical Efficacy and Safety in Diabetes Therapy. Eur Endocrinol. 2016 Mar;12(1):12-17. [PMC free article: PMC5813452] [PubMed: 29632581]

7.

Lepore M, Pampanelli S, Fanelli C, Porcellati F, Bartocci L, Di Vincenzo A, Cordoni C, Costa E, Brunetti P, Bolli GB. 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;49(12):2142-8. [PubMed: 11118018]

8.

Chan WB, Chen JF, Goh SY, Vu TTH, Isip-Tan IT, Mudjanarko SW, Bajpai S, Mabunay MA, Bunnag P. Challenges and unmet needs in basal insulin therapy: lessons from the Asian experience. Diabetes Metab Syndr Obes. 2017;10:521-532. [PMC free article: PMC5733912] [PubMed: 29276400]

9.

American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019 Jan;42(Suppl 1):S90-S102. [PubMed: 30559235]

10.

Horvath K, Jeitler K, Berghold A, Ebrahim SH, Gratzer TW, Plank J, Kaiser T, Pieber TR, Siebenhofer A. Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD005613. [PubMed: 17443605]

11.

Fournier M, Germe M, Theobald K, Scholz GH, Lehmacher W. Indirect comparison of lixisenatide versus neutral protamine Hagedorn insulin as add-on to metformin and sulphonylurea in patients with type 2 diabetes mellitus. Ger Med Sci. 2014;12:Doc14. [PMC free article: PMC4202665] [PubMed: 25332702]

12.

Blanco C, Castillo R, Quiralte J, Delgado J, García I, de Pablos P, Carrillo T. Anaphylaxis to subcutaneous neutral protamine Hagedorn insulin with simultaneous sensitization to protamine and insulin. Allergy. 1996 Jun;51(6):421-4. [PubMed: 8837667]

13.

Chu YQ, Cai LJ, Jiang DC, Jia D, Yan SY, Wang YQ. Allergic shock and death associated with protamine administration in a diabetic patient. Clin Ther. 2010 Sep;32(10):1729-32. [PubMed: 21194595]

14.

Belhekar MN, Pai S, Tayade P, Dalwadi P, Munshi R, Varthakavi P. A case of hypersensitivity to soluble and isophane insulins but not to insulin glargine. Indian J Pharmacol. 2015 Mar-Apr;47(2):227-9. [PMC free article: PMC4386139] [PubMed: 25878390]

Disclosure: Fatima Saleem declares no relevant financial relationships with ineligible companies.

Disclosure: Ashish Sharma declares no relevant financial relationships with ineligible companies.