NPH insulin (isophane)
The eighty-year-old basal insulin every modern analogue is measured against
NPH insulin is human insulin crystallised with protamine and zinc so it dissolves slowly. It is the cheapest basal insulin, the one analogues are compared with, and its absorption is more variable than the newer ones, which is the whole argument.
What is it?
NPH is not a modified insulin. It is ordinary human insulin crystallised with protamine, which must dissolve before absorption. That gives a peak and a duration without engineering the molecule, and it is why the suspension is cloudy and has to be mixed before use. The Humulin N label puts its peak serum level at about 4 hours and its maximum effect at about 6.5 hours, with wide ranges between individuals.
Its weakness was mapped long before the analogues existed. Absorption studies from the 1980s describe the variability, the effect of injecting into abnormal sites, and that exercise speeds absorption, which matters when the dose is meant to last the night. A 2015 clamp study added a modern one: an unmixed pen changed its duration of action from about 9 to 15 hours depending on how it was held.
The timing question has a clear old answer: bedtime NPH gave lower morning glucose, morning NPH lower evening glucose. Those are the trade-offs a flat analogue removes. In a direct clamp comparison at bedtime doses, glargine kept more glucose-lowering activity over 32 hours than NPH or detemir.
The evidence on what the analogues add is mixed. A 2020 Cochrane-style review is cautious about what they demonstrably add. When ACCORD participants were switched from glargine to NPH, severe hypoglycaemia more than doubled. Yet in preschool children glargine could not show non-inferiority on hypoglycaemia, and for steroid-induced hyperglycaemia in hospital the two worked equally well.
Pregnancy is where it long served as the reference. Detemir was compared with NPH in 310 women with type 1 diabetes and was non-inferior for HbA1c, with lower fasting glucose. NPH also has an emergency-room use under study: adding it early to the insulin drip in severe diabetic ketoacidosis shortened recovery in a 50-patient trial.
Human NPH insulin is sold by more than one manufacturer, and in some US states it can be bought without a prescription. The label calls for subcutaneous injection only, never intravenous use, and doses individualised to glucose monitoring.
Mechanism of Action
NPH is human insulin bound to protamine in crystals that dissolve slowly under the skin, giving an intermediate-acting insulin.
Protamine crystals
Crystals must dissolve before insulin is absorbed; the suspension is cloudy and must be resuspended before each dose.
A peak, not a plateau
Median peak effect about 6.5 hours after 0.4 unit/kg, range 2.8 to 13 hours (label 12.2).
Insulin receptor
Ordinary human insulin once absorbed; cleared mainly by the liver (label 12.3).
Published Research
These are the studies in people, read from their PubMed abstracts: absorption, timing, and the analogue comparison.
Bedtime or morning
In type 2 diabetes treated with a sulfonylurea, bedtime NPH produced lower morning blood glucose (7.8 against 9.1 mM, p < 0.01) while morning NPH produced lower evening glucose (10.1 against 12.1 mM, p < 0.01).
Mixing the vial matters
In type 1 diabetes, injecting NPH without resuspending it changed its duration of action (9.4 to 15.4 hours against 11.8 when mixed) and insulin levels.
Switching from glargine to NPH
In a subgroup of ACCORD participants switched from glargine to NPH, severe hypoglycaemia more than doubled (6.1 against 2.7 per 100 patient-years), HbA1c improved less and treatment satisfaction was lower.
Early NPH in diabetic ketoacidosis
In a 50-patient open-label trial, adding 0.25 IU/kg subcutaneous NPH to the insulin infusion shortened resolution of severe ketoacidosis (median 20 against 38.5 hours) and delayed rebound high glucose, without more hypoglycaemia.
NPH, glargine and detemir at bedtime
After a week of bedtime dosing in type 2 diabetes, glargine gave more glucose-lowering activity over 32 hours than NPH or detemir; two people on NPH and three on detemir stopped early because glucose rose above 150 mg/dL.
Type 1 diabetes in pregnancy
In 310 women with type 1 diabetes randomised before or early in pregnancy, detemir was non-inferior to NPH for HbA1c at 36 weeks (6.27% against 6.33%), with lower fasting glucose and similar hypoglycaemia.
Preschool children
In 125 children with type 1 diabetes averaging 4 years old, glargine once daily did not meet non-inferiority to NPH, mostly twice daily, for hypoglycaemia (1.93 against 1.69 composite events per 100 patient-years); differences were slight.
Steroid-induced high glucose
On a respiratory ward, glargine and NPH were equally effective as the basal insulin in a basal-bolus protocol for glucocorticoid-induced hyperglycaemia in type 2 diabetes, with a non-significant trend to fewer lows on glargine.
What the analogues actually add
A systematic review of long-acting and ultra-long-acting insulin analogues against NPH in adults with type 2 diabetes concluded that low-certainty evidence and trial designs not matching current practice leave it unclear whether the same effects appear in daily clinical practice, and that most trials did not report patient-relevant outcomes.
Exercise speeds it up
Exercise augmented the absorption of NPH insulin, one of the sources of day-to-day variability in how long a dose lasts.
Injecting into a lumpy site changes the dose
NPH injected into palpably abnormal (lipohypertrophic) sites gave about 22% worse blood glucose control than injection into normal thigh tissue, with markedly thicker, disrupted tissue at those sites.
Why an analogue caused weight loss
Comparing insulin detemir with NPH, detemir induced significant and sustained weight loss, first seen at one week, with a transient rise in urinary sodium excretion and a reduction in lean body mass, pointing at fluid handling rather than fat.
Dosing Data
NPH is injected under the skin, usually once or twice a day, with the dose set to glucose monitoring; it is often combined with a mealtime insulin.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
Side Effects & Contraindications
Reported Side Effects
The risks of basal insulin, with the variability that defines this one.
Contraindications & Cautions
Standard for insulin.
Legal Status
Long approved and sold without the newest patents.
Frequently Asked Questions
?What is NPH insulin?
Human insulin crystallised with protamine and zinc so that it dissolves slowly after injection. It is also called isophane insulin.
?Why is it cloudy?
Because it is a suspension of crystals rather than a solution, which is also why it has to be resuspended before each dose.
?Is it worse than the analogues?
It is more variable, and bedtime versus morning dosing visibly shifts which part of the day is covered. A 2020 review found the evidence that analogues improve patient-relevant outcomes in practice to be low-certainty.
?Why does it still matter?
It is the cheapest basal insulin and the comparator in most trials, so what a new insulin adds is usually measured against it.
?When does NPH peak?
The Humulin N label reports peak insulin levels at about 4 hours and maximum effect at about 6.5 hours, ranging from 2.8 to 13 hours between people.
?Is it safe in pregnancy?
It has long been a standard basal insulin in pregnancy; trials comparing detemir against it found similar HbA1c and hypoglycaemia, with lower fasting glucose on detemir.
References
- [pubmed] Groop LC, et al. "Morning or bedtime NPH insulin combined with sulfonylurea in treatment of NIDDM." Diabetes Care, 1992;15(7):831-4. PMID: 1516500.
- [pubmed] Semlitsch T, et al. "(Ultra-)long-acting insulin analogues versus NPH insulin (human isophane insulin) for adults with type 2 diabetes mellitus." Cochrane Database Syst Rev, 2020;11(11):CD005613. PMID: 33166419.
- [pubmed] Thow JC, et al. "Exercise augments the absorption of isophane (NPH) insulin." Diabet Med, 1989;6(4):342-5. PMID: 2524341.
- [pubmed] Thow JC, et al. "Morphology of palpably abnormal injection sites and effects on absorption of isophane(NPH) insulin." Diabet Med, 1990;7(9):795-9. PMID: 2148131.
- [pubmed] Hendriksen KV, et al. "Effects of insulin detemir and NPH insulin on renal handling of sodium, fluid retention and weight in type 2 diabetic patients." Diabetologia, 2012;55(1):46-50. PMID: 22002075.
- [pubmed] Hagedorn HC. "Protamine Insulinate: (Section of Therapeutics and Pharmacology)." Proc R Soc Med, 1937;30(6):805-14. PMID: 19991109.
- [fda-pi] FDA. Humulin N (NPH insulin) prescribing information. Eli Lilly.
- [clinical-trial] Lucidi P, et al. "Pharmacokinetics and Pharmacodynamics of NPH Insulin in Type 1 Diabetes: The Importance of Appropriate Resuspension Before Subcutaneous Injection." Diabetes Care, 2015;38(12):2204-10. PMID: 26358287.
- [pubmed] Berard L, et al. "Replacing Insulin Glargine with Neutral Protamine Hagedorn (NPH) Insulin in a Subpopulation of Study Subjects in the Action to Control Cardiovascular Risk in Diabetes (ACCORD): Effects on Blood Glucose Levels, Hypoglycemia and Patient Satisfaction." Can J Diabetes, 2015;39(4):296-301. PMID: 25819531.
- [clinical-trial] Baby N, et al. "Early use of neutral Protamine Hagedorn (NPH) insulin in the management of diabetic ketoacidosis: an open-label randomized controlled trial in a resource-limited setting." BMC Res Notes, 2025;18(1):471. PMID: 41199369.
- [clinical-trial] Lucidi P, et al. "Pharmacokinetics and pharmacodynamics of therapeutic doses of basal insulins NPH, glargine, and detemir after 1 week of daily administration at bedtime in type 2 diabetic subjects: a randomized cross-over study." Diabetes Care, 2011;34(6):1312-4. PMID: 21498786.
- [clinical-trial] Mathiesen ER, et al. "Maternal efficacy and safety outcomes in a randomized, controlled trial comparing insulin detemir with NPH insulin in 310 pregnant women with type 1 diabetes." Diabetes Care, 2012;35(10):2012-7. PMID: 22851598.
- [clinical-trial] Danne T, et al. "A randomized trial comparing the rate of hypoglycemia--assessed using continuous glucose monitoring--in 125 preschool children with type 1 diabetes treated with insulin glargine or NPH insulin (the PRESCHOOL study)." Pediatr Diabetes, 2013;14(8):593-601. PMID: 23730996.
- [clinical-trial] Ruiz de Adana MS, et al. "Randomized clinical trial of the efficacy and safety of insulin glargine vs. NPH insulin as basal insulin for the treatment of glucocorticoid induced hyperglycemia using continuous glucose monitoring in hospitalized patients with type 2 diabetes and respiratory disease." Diabetes Res Clin Pract, 2015;110(2):158-65. PMID: 26474657.
- [fda-pi] Humulin N (human insulin isophane suspension) US prescribing information (Eli Lilly; DailyMed set f6edd793, effective December 19, 2025), sections 2.1-2.3, 12.2 and 12.3; read through openFDA October 6, 2026.
Sources & Citations
Studies were read from their PubMed abstracts; the Humulin N label from DailyMed (set f6edd793, effective December 19, 2025) through openFDA, read October 6, 2026.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.