Skip to content
type1.science

NPH insulin (isophane / Humulin N / Novolin N)

Eli Lilly (Humulin N); Novo Nordisk (Novolin N / ReliOn)

The legacy intermediate-acting human (non-analog) basal insulin, and by far the cheapest and most accessible — sold behind the pharmacy counter without a prescription in most US states at a notably low cost. It works, but it has a pronounced 4-8 hour peak that drives nocturnal hypoglycemia and noticeably more day-to-day variability than modern basal analogs.

Available nowRegulator-approvedbasallong-acting

The scorecard

Onset speed50

Basal-role convention: onset is not the goal. NPH does begin lowering glucose at ~1-2 h, but for a background insulin this is scored neutrally against basal peers.[^4][^5]

Time to peak28

Basal-role convention (flat scores HIGH): NPH is the opposite of flat — a pronounced peak at ~4-6.5 h. That peak is its core weakness vs peakless glargine/degludec, so it scores LOW.[^1][^2]

Short tail42

Basal-role convention (smooth ~24 h coverage scores HIGH): action wanes by ~14-18 h, so it rarely covers a full day and usually needs twice-daily dosing plus a bedtime dose.[^1][^4]

Consistency35

A cloudy suspension needing resuspension each time, with higher within- and between-person absorption variability than glargine in clamp studies — its least predictable feature.[^1][^3]

Exercise flexibility38

The fixed mid-action peak can collide with afternoon/overnight exercise to cause lows, and the long suspension depot cannot be quickly dialed back; absorption itself shifts with physical activity.[^2][^5]

Access & cost95

The standout strength: notably low-cost, available behind the pharmacy counter without a prescription in nearly every US state, and on the WHO Essential Medicines List worldwide.[^7][^8][^9]

Insulins are scored relative to their role peers (see tags: rapid, ultra-rapid, basal, inhaled). A basal insulin's onset score compares it to other basals, not to mealtime insulins.

The full picture

NPH (Neutral Protamine Hagedorn), also called isophane insulin, is an intermediate-acting basal (background) human insulin — not a modern analog. It is the same human insulin sequence made by recombinant DNA, but suspended with protamine and zinc so it forms crystals that dissolve slowly under the skin, stretching one injection across part of a day.12 Brand names are Humulin N (Eli Lilly) and Novolin N (Novo Nordisk, also sold as Walmart's ReliOn).

Role and how it's used. NPH is a basal insulin, but unlike flat modern basals it has a distinct peak, so people often use it twice daily and time a dose at bedtime to cover the overnight fasting period. Mealtime coverage still needs a separate rapid or regular insulin.3

PK/PD with real numbers. After a subcutaneous dose, NPH begins lowering glucose at about 1-2 hours.1 Its hallmark is a peak: in healthy subjects the median peak insulin concentration is at ~4 hours (range 1-12 h) and the median peak effect at ~6.5 hours (range 2.8-13 h).4 In a 24-hour clamp study in type 1 diabetes, NPH showed onset ~0.8 h, peak action ~4.5 h, and end of action ~14 hours — versus a peakless ~22-hour profile for glargine.5 Real-world labeling describes duration as roughly 12-18 (up to 24) hours, dose-dependent.12

Absorption variability. As a cloudy suspension, NPH must be resuspended (gently rolled/rocked) before every dose or the delivered amount varies.12 Even when mixed correctly, its day-to-day and person-to-person absorption is more variable than glargine in head-to-head clamp data — a key reason analogs displaced it.56 That mid-action peak, landing in the early-morning hours after a bedtime dose, is the main driver of nocturnal hypoglycemia.5

Behaviour around exercise. Physical activity speeds insulin absorption, and the fixed NPH peak can coincide with exercise or overnight recovery to cause lows; the slow suspension depot cannot be quickly reduced once injected, so planning ahead matters more than with adjustable analogs.52

Delivery. Subcutaneous injection only (abdomen, thigh, upper arm, buttocks). It must not be given intravenously and must not be used in an insulin pump.1 It comes as U-100 10 mL vials and prefilled pens (Humulin N KwikPen; Novolin N FlexPen).12

Approvals. Recombinant human insulin (Humulin) was the first FDA-approved recombinant DNA drug, cleared in 1982 (Eli Lilly, using Genentech technology).7 Novolin N's initial US approval dates to 1991.2 NPH remains approved across the US, UK, EU, Canada, Australia and Japan.

Access, cost, biosimilars. This is NPH's reason to exist. Human insulins like NPH are sold behind the pharmacy counter without a prescription across the US — for example Walmart's ReliOn Novolin N.89 Indiana was the last state to require a prescription for human insulin, removing that requirement effective January 1, 2021, which brought it in line with the rest of the country.9 As a non-analog human insulin it has no "biosimilars" in the analog sense, but multiple interchangeable brands and the WHO Essential Medicines listing make it the global low-cost/access option.10

What's coming. NPH is a mature product with no meaningful pipeline of its own — the trajectory is the opposite: modern basal analogs (glargine, detemir, degludec) match NPH on HbA1c, with detemir showing lower severe hypoglycemia than NPH (though the evidence is less clear for severe nocturnal hypoglycemia, where the difference was not statistically significant), and falling analog prices (capped copays, low-cost analog programs, biosimilars) are steadily eroding NPH's one advantage.5311 Its enduring role is as the affordable safety net when analogs are unaffordable or unavailable, not as a target for improvement.

References

  1. U.S. Food and Drug Administration / Eli Lilly. HUMULIN N (insulin human) injectable suspension — Full Prescribing Information (resuspension; not for intravenous or insulin-pump use; U-100 10 mL vial and KwikPen). Drugs@FDA label (2022). https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/018781s193lbl.pdf ↩ ↩2 ↩3 ↩4 ↩5 ↩6

  2. U.S. Food and Drug Administration / Novo Nordisk. NOVOLIN N (insulin isophane human) injectable suspension — Prescribing Information (Initial U.S. Approval: 1991; FlexPen). DailyMed / FDA label (accessed 2026). https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=82f1445c-b2c6-445a-82cf-ba8825fac776 ↩ ↩2 ↩3 ↩4 ↩5 ↩6

  3. Kalra S, Gupta Y. NPH insulin and intermediate-acting basal insulin — role and dosing. NPH Insulin, StatPearls (NCBI Bookshelf, accessed 2026). Onset 1–3 h, peak 4–8 h, duration ~14–24 h; typically dosed twice daily (morning and evening/bedtime). https://www.ncbi.nlm.nih.gov/books/NBK549860/ ↩ ↩2

  4. U.S. Food and Drug Administration / Eli Lilly. HUMULIN N (insulin human) injection, suspension — Prescribing Information. DailyMed / FDA label (accessed 2026). Median peak serum insulin concentration ~4 h (range 1–12 h); median maximum glucose-lowering effect at 6.5 h (range 2.8–13 h). https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6edd793-440b-40c2-96b5-c16133b7a921 ↩

  5. Lepore M, Pampanelli S, Fanelli C, 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). PubMed PMID 11118018. https://doi.org/10.2337/diabetes.49.12.2142 ↩ ↩2 ↩3 ↩4 ↩5

  6. Heise T, Nosek L, Rønn BB, et al. Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes (2004). PubMed PMID 15161770. https://doi.org/10.2337/diabetes.53.6.1614 ↩

  7. U.S. Food and Drug Administration / Eli Lilly. Humulin (recombinant human insulin) — first recombinant-DNA therapeutic approved by the FDA, October 1982. Endocrine Reviews (2021), historical review of the path to Humulin. https://doi.org/10.1210/endrev/bnaa029 ↩

  8. GoodRx / Walmart ReliOn. Human insulin (Novolin N / ReliOn) is sold over the counter without a prescription at low cost (e.g., Walmart ReliOn ~$25/vial). GoodRx drug information (accessed 2026). https://www.goodrx.com/humulin-n/what-is ↩

  9. Indiana House Republicans. Kirchhofer: House approves bill making (human) insulin available without prescription — bringing Indiana "in line with the rest of the country"; effective January 1, 2021. Press release (2020). https://www.indianahouserepublicans.com/news/press-releases/kirchhofer-house-approves-bill-making-insulin-available-without-prescription/ ↩ ↩2

  10. World Health Organization. WHO Model List of Essential Medicines — insulin (human, intermediate-acting / isophane NPH). WHO (accessed 2026). https://www.who.int/publications/i/item/WHO-MHP-HPS-EML-2023.02 ↩

  11. Hemmingsen B, Metzendorf MI, Richter B. (Ultra-)long-acting insulin analogues for people with type 1 diabetes mellitus. Cochrane Database Syst Rev (2021). Insulin detemir vs NPH: lower severe hypoglycaemia (RR 0.69); severe nocturnal hypoglycaemia not significantly different. PubMed PMID 33662147. https://doi.org/10.1002/14651858.CD013498.pub2 ↩