How does NPH compare with newer basal analogues?

Meta-analyses show similar HbA1c control, but NPH tends to cause more hypoglycaemia, especially at night; its main advantage is much lower cost.

Why does NPH need to be mixed before injecting?

It is a cloudy suspension that settles, so it must be gently resuspended (rolled, not shaken) before each dose to deliver a consistent amount.

Is NPH available without a prescription?

In the United States, Humulin N and Novolin N can be bought over the counter at many pharmacies, but you should still use it only under a clinician's guidance because of hypoglycaemia risk.

What is the main risk of NPH insulin?

Hypoglycaemia, which can be severe and is more frequent than with long-acting analogues; weight gain, injection-site reactions and low potassium can also occur. Dosing must be individualized.

EMA-approvedaka Isophane insulin, Humulin N, Novolin N

NPH insulin — Complete Research Guide (2026)

Last updated 2026-06-30

TL;DR

NPH insulin (also known as Isophane insulin) is a peptide catalogued under Hormones & Metabolic (Intermediate-acting insulin). It is described as: Insulin receptor agonist. Documented context: Diabetes mellitus. Neutral reference entry; EU status: EU-approved prescription medicine.

What is NPH insulin?

NPH insulin (neutral protamine Hagedorn, or isophane insulin; brands such as Humulin N and Novolin N) is an intermediate-acting human insulin in which protamine is added to slow absorption, giving a basal effect that lasts roughly half a day. It is a long-established, approved human insulin still widely used for type 1 and type 2 diabetes, and in the United States is available without a prescription at many pharmacies.

The evidence base is large and human, including numerous randomized trials and Cochrane systematic reviews comparing NPH with newer long-acting analogues; it remains a low-cost basal option.

How does NPH insulin work?

Protamine complexes with insulin to form a crystalline suspension that dissolves and absorbs slowly after subcutaneous injection, producing an intermediate-duration basal insulin with a pronounced peak.

Once absorbed it acts on the insulin receptor to lower blood glucose by increasing tissue uptake and reducing hepatic glucose output.

What does the research say about NPH insulin?

NPH achieves HbA1c reductions broadly similar to long-acting analogues, making it an effective and much cheaper basal insulin option. ^[1]
Meta-analysis confirms comparable glycaemic control with NPH versus (ultra-)long-acting analogues in type 2 diabetes, the main trade-off being more hypoglycaemia with NPH. ^[2]
Network meta-analysis found no clear HbA1c advantage of analogues over NPH, supporting NPH as a reasonable basal choice where cost matters. ^[4]

Clinical research & studies

The references below are the primary sources cited throughout this guide. Each links directly to PubMed or the regulator. Where evidence is preclinical (animal or in-vitro), that is stated rather than implied.

[1] Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus — Horvath K et al., Cochrane Database of Systematic Reviews 2007. (Systematic review / meta-analysis)
[2] (Ultra-)long-acting insulin analogues versus NPH insulin (human isophane insulin) for adults with type 2 diabetes mellitus — Semlitsch T et al., Cochrane Database of Systematic Reviews 2020. (Systematic review / meta-analysis)
[3] (Ultra-)long-acting insulin analogues for people with type 1 diabetes mellitus — Hemmingsen B et al., Cochrane Database of Systematic Reviews 2021. (Systematic review / meta-analysis)
[4] Safety, effectiveness, and cost effectiveness of long acting versus intermediate acting insulin for patients with type 1 diabetes: systematic review and network meta-analysis — Tricco AC et al., BMJ 2014. (Network meta-analysis)
[5] Efficacy and safety of different basal and prandial insulin analogues for the treatment of type 2 diabetes: a network meta-analysis of randomized controlled trials — Mannucci E et al., Endocrine 2021. (Network meta-analysis)
[6] A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes — Hermansen K et al., Diabetes Care 2006. (Randomized controlled trial)

Dosing context

This is not medical advice or a usage recommendation. Dosing figures are reported research context only, cited from the published literature.

NPH is injected subcutaneously once or twice daily as basal insulin, often at bedtime and/or morning, and is titrated to fasting glucose under medical supervision. This encyclopedia provides context only, not dosing instructions.

Because it is a suspension with a peak effect, timing relative to meals and consistent resuspension matter; any change in product or regimen should be guided by a clinician.

Side effects & safety profile

Hypoglycaemia is the main and potentially severe risk, and NPH carries a higher rate of overall and nocturnal hypoglycaemia than long-acting analogues, partly because of its pronounced peak; weight gain, injection-site reactions and hypokalaemia can also occur.

Its suspension must be gently resuspended before each dose, and its variable absorption makes careful, individualized titration important.

Dosing is set and adjusted by a clinician based on glucose targets, diet and activity; NPH must not be interchanged unit-for-unit with analog insulins without professional guidance.

Stacking & combinations

NPH is commonly used as the basal insulin within a basal-bolus regimen alongside a rapid-acting mealtime insulin, or combined with oral agents, always under clinical supervision.

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Frequently asked questions

NPH (isophane) is an intermediate-acting human insulin that uses protamine to slow absorption, providing basal glucose control for roughly half a day; brands include Humulin N and Novolin N.

References

[1] Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus — Horvath K et al., Cochrane Database of Systematic Reviews 2007. PMID: 17443605. View sourceStudy: Systematic review / meta-analysisAnalogues offered little HbA1c benefit over NPH but reduced symptomatic and nocturnal hypoglycaemia.
[2] (Ultra-)long-acting insulin analogues versus NPH insulin (human isophane insulin) for adults with type 2 diabetes mellitus — Semlitsch T et al., Cochrane Database of Systematic Reviews 2020. PMID: 33166419. View sourceStudy: Systematic review / meta-analysisGlycaemic control was similar to NPH while analogues modestly lowered hypoglycaemia risk.
[3] (Ultra-)long-acting insulin analogues for people with type 1 diabetes mellitus — Hemmingsen B et al., Cochrane Database of Systematic Reviews 2021. PMID: 33662147. View sourceStudy: Systematic review / meta-analysisIn type 1 diabetes, long-acting analogues showed small hypoglycaemia benefits over NPH with comparable HbA1c.
[4] Safety, effectiveness, and cost effectiveness of long acting versus intermediate acting insulin for patients with type 1 diabetes: systematic review and network meta-analysis — Tricco AC et al., BMJ 2014. PMID: 25274009. View sourceStudy: Network meta-analysisLong-acting analogues gave only modest advantages over NPH, questioning their cost-effectiveness in type 1 diabetes.
[5] Efficacy and safety of different basal and prandial insulin analogues for the treatment of type 2 diabetes: a network meta-analysis of randomized controlled trials — Mannucci E et al., Endocrine 2021. PMID: 34599695. View sourceStudy: Network meta-analysisBasal analogues reduced hypoglycaemia relative to NPH with similar overall glycaemic efficacy in type 2 diabetes.
[6] A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes — Hermansen K et al., Diabetes Care 2006. PMID: 16732007. View sourceStudy: Randomized controlled trialNPH matched detemir for glycaemic control but caused more weight gain and hypoglycaemia.

This article is for educational and research purposes only. Peptides discussed here are not approved for human consumption by the FDA, EMA, or equivalent regulators outside of specific clinical contexts. Always consult a licensed medical professional before any therapeutic use.