Insulin aspart

What it is

Insulin aspart is a manufactured analogue of human insulin in which one amino acid is changed so that it is absorbed faster from under the skin than regular human insulin. It is given by subcutaneous injection or infusion, or intravenously in hospital. Its label states the maximum glucose-lowering effect occurs between 1 and 3 hours after a subcutaneous dose and that the duration of action is 3 to 5 hours. It is used as the mealtime (bolus) part of an insulin regimen alongside a longer-acting basal insulin, or in an insulin pump.

What the research says

The evidence is that insulin aspart does the same job as regular human insulin, slightly better on average and slightly faster, not that it is a different kind of treatment. A systematic review of 28 randomised trials found a small advantage in glycated haemoglobin in type 1 diabetes (weighted mean difference -0.11%), clear improvements in after-meal glucose, no difference in fasting glucose, and no significant HbA1c advantage in type 2 diabetes. The same review found slightly more hypoglycaemic episodes overall with insulin aspart, and no difference in severe or nocturnal hypoglycaemia. Most of the trials were unblinded and only four of 28 had adequate allocation concealment.

Evidence grade: Well established.

How it works

Drug class: Rapid-acting human insulin analogue (short-acting insulin analogue)

Insulin aspart acts like the body's own insulin: it makes muscle and fat tissue take glucose out of the blood and it stops the liver making new glucose, which lowers blood sugar. It also stops fat and protein being broken down for fuel and promotes protein building. The single amino acid substitution makes it absorb faster from the injection site than regular human insulin, so it works closer to the timing of a meal. (Source 1)

What it is used for

• In type 1 diabetes, insulin aspart lowered glycated haemoglobin slightly more than regular human insulin (WMD -0.11%, 95% CI -0.16 to -0.06 across 13 trials) and improved after-meal glucose by roughly 1 to 1.4 mmol/L, with no difference in fasting glucose. The advantage is small and most trials were unblinded. Evidence: established. (Source 2)
• In type 2 diabetes the same systematic review found no significant difference in glycated haemoglobin between insulin aspart and regular human insulin across 11 trials, although after-meal glucose was better. There was no difference in the risk of any type of hypoglycaemic episode. Evidence: limited. (Source 3)
• A Cochrane review of five randomised trials (201 participants, only one of them using insulin aspart, 45 participants) found time to resolution of ketoacidosis of about 11 hours either way and comparable hypoglycaemia, on mostly low to very low quality evidence. Using subcutaneous insulin aspart in place of an intravenous insulin infusion for ketoacidosis is not an approved use. Evidence: limited. (Source 4)

Interactions

• Alcohol (label): Alcohol can either strengthen or weaken insulin's blood-glucose-lowering effect, so glucose can swing in either direction when alcohol is drunk while using insulin aspart. (Source 5)
• Salicylates (including aspirin-type compounds) and sulfonamide antibiotics (label): These are listed by the manufacturer among the drugs that may increase the risk of low blood sugar when taken with insulin aspart. (Source 6)
• Beta-blockers, clonidine, guanethidine and reserpine (label): These drugs can blunt the warning signs of low blood sugar, so a hypoglycaemic episode may be felt less clearly or not at all. (Source 7)
• Niacin (nicotinic acid) and other agents that raise blood glucose (label): Niacin is listed by the manufacturer among the drugs that may decrease insulin aspart's blood-glucose-lowering effect, so blood glucose may run higher; the label groups niacin with corticosteroids, thyroid hormones, oestrogens and atypical antipsychotics in that row. (Source 8)

Stopping it

• There is no dependence or withdrawal syndrome described for insulin aspart, but stopping insulin in insulin-dependent diabetes is dangerous rather than neutral: missed or omitted insulin is one of the recognised causes of diabetic ketoacidosis, an acute life-threatening state. (Source 9)
• Because the drug's action is short, its glucose-lowering effect fades within hours of a dose rather than persisting, which is why doses are repeated at meals rather than tapered. (Source 10)

What goes wrong

Insulin aspart was associated with a slightly higher risk of having a hypoglycaemic episode than regular human insulin in type 1 diabetes, with no difference in severe or night-time episodes. (Source 2)

• Systematic review, Low certainty.
• Size: Six randomised controlled trials for this outcome.
• Who: People with type 1 diabetes mellitus.
• How long: Not stated in the record.
• Result: RR 1.06, 95% CI 1.01 to 1.10 for any hypoglycaemic episode; no difference for nocturnal or severe hypoglycaemia.
• Funding: not stated.

There was an increased risk of hypoglycaemic episode with insulin aspart (RR 1.06, 95% CI 1.01 to 1.10; six RCTs) but no difference in the risk of nocturnal or severe hypoglycaemic episodes.

Insulin deficiency, including from missed insulin doses, drives the chain of events that produces diabetic ketoacidosis. (Source 9)

• Expert review, not systematic, Certainty not rated.
• Size: Not applicable; clinical review.
• Who: People with diabetes mellitus presenting with ketoacidosis.
• How long: Not applicable.
• Result: No effect estimate; describes insulin noncompliance as one of the causes of diabetic ketoacidosis and the resulting hyperglycaemia, dehydration and metabolic acidosis.
• Funding: not stated.

DKA results from insulin deficiency from new-onset diabetes, insulin noncompliance, prescription or illicit drug use, and increased insulin need because of infection.

What the evidence supports

In type 1 diabetes, insulin aspart produced a small but statistically significant reduction in glycated haemoglobin compared with regular human insulin. (Source 2)

• Systematic review, Low certainty.
• Size: 13 randomised controlled trials within a review of 28 RCTs (total participant number not reported in the record)
• Who: Adults and children with type 1 diabetes mellitus.
• How long: Trials of varying length; not stated in the record.
• Result: WMD -0.11%, 95% CI -0.16 to -0.06; stratified by regimen, -0.31% (95% CI -0.55 to -0.08) for continuous subcutaneous insulin infusion and -0.12% (95% CI -0.17 to -0.06) for basal bolus, with no significant difference for premixed insulins.
• Funding: not stated.

Insulin aspart resulted in a significant decrease in glycated haemoglobin levels (WMD -0.11%, 95% CI -0.16 to -0.06

Insulin aspart improved glucose readings after breakfast, lunch and dinner compared with regular human insulin in type 1 diabetes. (Source 2)

• Systematic review, Low certainty.
• Size: Five to six randomised controlled trials per outcome.
• Who: People with type 1 diabetes mellitus.
• How long: Not stated in the record.
• Result: Post-breakfast glucose WMD -1.43 mmol/L (95% CI -1.75, -1.11); post-lunch -1.11 mmol/L (-1.61 to -0.61); post-dinner -0.97 mmol/L (-1.25 to -0.69)
• Funding: not stated.

Insulin aspart was associated with improvements in post-breakfast glucose (WMD -1.43mmol/L, 95% CI -1.75, -1.11; five RCTs)

What the evidence does not support

In type 2 diabetes, insulin aspart did not lower glycated haemoglobin significantly more than regular human insulin. (Source 3)

• Systematic review, Low certainty.
• Size: 11 randomised controlled trials in people with type 2 diabetes.
• Who: Adults with type 2 diabetes mellitus.
• How long: Not stated in the record.
• Result: No significant difference overall; after excluding one trial, WMD -0.10%, 95% CI -0.19 to -0.02 across eight RCTs.
• Funding: not stated.

There were no significant differences in glycated haemoglobin levels between insulin aspart and regular human insulin groups

Insulin aspart did not improve fasting glucose compared with regular human insulin in either type 1 or type 2 diabetes. (Source 2)

• Systematic review, Low certainty.
• Size: 28 randomised controlled trials in total.
• Who: People with type 1 or type 2 diabetes mellitus.
• How long: Not stated in the record.
• Result: No significant difference in fasting glucose levels in either diabetes type.
• Funding: not stated.

but there was no significant difference in fasting glucose levels compared with regular human insulin

Where the evidence is mixed

The trial evidence comparing insulin aspart with regular human insulin is mostly unblinded, which the review itself flags as a quality limitation. (Source 11)

• Systematic review, Low certainty.
• Size: 28 randomised controlled trials.
• Who: People with type 1 or type 2 diabetes mellitus.
• How long: Not stated in the record.
• Result: Only four of 28 trials were double blinded and only four had adequate concealment of treatment allocation.
• Funding: not stated.

Only four trials were double blinded and only four had adequate concealment of treatment allocation.

For mild to moderate diabetic ketoacidosis, subcutaneous rapid-acting insulin analogues resolved ketoacidosis in about the same time as intravenous regular insulin, on low to very low quality evidence. (Source 4)

• Systematic review, Very low certainty.
• Size: Five randomised controlled trials, 201 participants (one trial of insulin aspart, 45 participants)
• Who: Mainly adults with mild or moderate diabetic ketoacidosis; children underrepresented.
• How long: Mean hospital stay two to seven days; evidence current to October 2015.
• Result: Time to resolution approximately 11 hours in both groups; hypoglycaemic episodes 118 per 1000 with intravenous insulin versus 70 per 1000 with subcutaneous lispro (not statistically significant); no deaths.
• Funding: not stated.

Time to resolution of diabetic ketoacidosis from the start of therapy did not differ substantially between the two insulin treatment schemes (approximately 11 hours).

Where the research disagrees

How much hypoglycaemia risk differs between rapid-acting insulin analogues and regular human insulin

• Rys and colleagues, systematic review of 28 randomised trials (2011), systematic-review of randomised trials in routine diabetes care: There was an increased risk of hypoglycaemic episode with insulin aspart (RR 1.06, 95% CI 1.01 to 1.10; six RCTs) but no difference in the risk of nocturnal or severe hypoglycaemic episodes. (Source 2)
• Andrade-Castellanos and colleagues, Cochrane review of subcutaneous analogues in diabetic ketoacidosis (2016), systematic-review of five small randomised trials in a hospital setting, rated low to very low quality: Hypoglycaemic (low blood sugar) episodes were comparable: 118 per 1000 participants for intravenous insulin compared with 70 per 1000 participants for subcutaneous insulin lispro (no statistically significant difference). (Source 4)

How much

• Reference intake: There is no reference intake for insulin aspart: the dose is set by the prescriber and titrated to blood glucose. The manufacturer's label (a position, the DailyMed record revised 02/2023) states that absorption and onset vary with injection site, exercise and other variables, so no fixed amount applies to everyone. (Source 10)
• Upper limit: No upper limit or maximum daily dose is stated in the label passages we recorded; the label sets no ceiling and instead describes individual variability in the time course of action. (Source 10)
• Studied: The manufacturer's pharmacodynamic study gave 0.15 units/kg subcutaneously to 22 patients with type 1 diabetes. (Source 10)
• Studied: The trials pooled in the 2011 systematic review gave insulin aspart as a basal-bolus regimen, as continuous subcutaneous insulin infusion (pump), or as premixed insulin. (Source 2)

A common belief, and what the research shows

The belief: Rapid-acting analogue insulins such as insulin aspart control diabetes far better than the older human insulins they replaced.

What the research shows: The measured difference is small. The pooled systematic review reports "Insulin aspart resulted in a significant decrease in glycated haemoglobin levels (WMD -0.11%, 95% CI -0.16 to -0.06" in type 1 diabetes, and in type 2 diabetes "There were no significant differences in glycated haemoglobin levels between insulin aspart and regular human insulin groups". The same review also reports "There was an increased risk of hypoglycaemic episode with insulin aspart (RR 1.06, 95% CI 1.01 to 1.10; six RCTs) but no difference in the risk of nocturnal or severe hypoglycaemic episodes." The gains are in after-meal glucose and convenience, on largely unblinded trials.

Questions and answers

What is it?

Insulin aspart is a laboratory-made version of human insulin, altered by one amino acid so it is absorbed faster from under the skin. It is injected or infused rather than swallowed. Its effect peaks between one and three hours after a subcutaneous dose and lasts about three to five hours, which is why it is used at mealtimes. (Source 10)

What does it do in the body?

It does what the body's own insulin does. It makes muscle and fat tissue pull glucose out of the blood and it stops the liver from releasing new glucose, which brings blood sugar down. It also stops fat and protein being broken down for fuel and helps protein be built. (Source 1)

Is it good or bad for you?

For someone who needs insulin it is necessary, and compared with older regular human insulin it gives slightly better average glucose control in type 1 diabetes and better after-meal readings. The trade-off measured in the same trials is slightly more hypoglycaemic episodes overall, though not more severe or night-time episodes. In type 2 diabetes the average HbA1c advantage was not significant. (Source 2)

How do you get more of it?

Insulin aspart is a prescription-only injectable medicine; there is no dietary or behavioural way to obtain it. In the trials it was given either as mealtime injections alongside a longer-acting basal insulin, as a continuous infusion through a pump, or as part of a premixed insulin. The amount is set by a prescriber and adjusted to blood glucose readings. (Source 2)

If it is harmful, what reduces it?

There is no way to remove insulin aspart once injected; its action simply wears off. The label puts the duration of action at three to five hours, with the peak effect between one and three hours, so an excessive effect is time-limited rather than permanent. Clinical management of a low blood sugar episode was not covered in the sources we recorded. (Source 10)

Why might someone be low in it or missing it?

Someone lacks insulin action either because their pancreas makes little or none, as in autoimmune type 1 diabetes, or because they have stopped taking prescribed insulin, or because illness or infection has raised their insulin requirement above what they are taking. All three appear in the literature as routes into diabetic ketoacidosis. (Source 9)

Which whole foods contain it or feed it?

No whole food contains insulin aspart. It is a manufactured analogue that has to be injected or infused, because it would be digested if swallowed; the label describes it only as a subcutaneous or intravenous injection. Food matters to it in a different way: the drug is timed around meals because it acts on the glucose that comes from carbohydrate in food. (Source 10)

What happens if you do not have it?

Without enough insulin action the body cannot use glucose, so counter-regulatory hormones rise, fat is broken down into ketones, protein and glycogen are broken down to make more glucose, and blood sugar climbs. The result is dehydration from osmotic diuresis, metabolic acidosis and, untreated, a life-threatening state called diabetic ketoacidosis. (Source 9)

How can you test for it?

You do not test for insulin aspart itself in routine care. What is measured is its effect: blood glucose readings, and glycated haemoglobin as the medium-term average, which is the outcome the trials used. The label repeatedly directs that glucose monitoring be increased when anything is likely to change insulin's effect, which is an indirect acknowledgement that the drug's effect is judged from glucose, not from drug levels. (Source 7)

References

1. DailyMed, U.S. National Library of Medicine (Novo Nordisk Inc. label). NOVOLOG (insulin aspart) injection, for subcutaneous or intravenous use - full prescribing information, section 12.1 Mechanism of Action (label Revised: 2/2023). 2023. Read the source
2. Diabetes and Metabolism (record in Database of Abstracts of Reviews of Effects, Centre for Reviews and Dissemination). Efficacy and safety comparison of rapid-acting insulin aspart and regular human insulin in the treatment of type 1 and type 2 diabetes mellitus: a systematic review. 2011. PMID 21333580. Read the source
3. Diabetes and Metabolism (record in Database of Abstracts of Reviews of Effects, Centre for Reviews and Dissemination). Efficacy and safety comparison of rapid-acting insulin aspart and regular human insulin in the treatment of type 1 and type 2 diabetes mellitus: a systematic review. 2011. PMID 21333580. Read the source
4. Cochrane Database of Systematic Reviews (Cochrane plain-language record). Subcutaneous rapid-acting insulin analogues for diabetic ketoacidosis. 2016. PMID 26798030, DOI 10.1002/14651858.CD011281.pub2. Read the source
5. DailyMed, U.S. National Library of Medicine (Novo Nordisk Inc. label). NOVOLOG (insulin aspart) injection, for subcutaneous or intravenous use - full prescribing information, section 7 Drug Interactions, interactions table row "Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of NOVOLOG" (label Revised: 2/2023). The row label, the drugs cell and the intervention cell are recorded on separate lines; this is a table row, not running prose, and no quote taken from it crosses from one cell into another.. 2023. Read the source
6. DailyMed, U.S. National Library of Medicine (Novo Nordisk Inc. label). NOVOLOG (insulin aspart) injection, for subcutaneous or intravenous use - full prescribing information, section 7 Drug Interactions, interactions table row "Drugs That May Increase the Risk of Hypoglycemia" (label Revised: 2/2023). The row label, the drugs cell and the intervention cell are recorded on separate lines; this is a table row, not running prose, and no quote taken from it crosses from one cell into another.. 2023. Read the source
7. DailyMed, U.S. National Library of Medicine (Novo Nordisk Inc. label). NOVOLOG (insulin aspart) injection, for subcutaneous or intravenous use - full prescribing information, section 7 Drug Interactions, interactions table row "Drugs That May Blunt Signs and Symptoms of Hypoglycemia" (label Revised: 2/2023). The row label, the drugs cell and the intervention cell are recorded on separate lines; this is a table row, not running prose, and no quote taken from it crosses from one cell into another.. 2023. Read the source
8. DailyMed, U.S. National Library of Medicine (Novo Nordisk Inc. label). NOVOLOG (insulin aspart) injection, for subcutaneous or intravenous use - full prescribing information, section 7 Drug Interactions, interactions table row "Drugs That May Decrease the Blood Glucose Lowering Effect of NOVOLOG" (label Revised: 2/2023). The row label, the drugs cell and the intervention cell are recorded on separate lines; this is a table row, not running prose, and no quote taken from it crosses from one cell into another.. 2023. Read the source
9. American Family Physician. Diabetic Ketoacidosis: Evaluation and Treatment. 2013. PMID 23547550. Read the source
10. DailyMed, U.S. National Library of Medicine (Novo Nordisk Inc. label). NOVOLOG (insulin aspart) injection, for subcutaneous or intravenous use - full prescribing information, section 12.2 Pharmacodynamics (label Revised: 2/2023). 2023. Read the source
11. Diabetes and Metabolism (record in Database of Abstracts of Reviews of Effects, Centre for Reviews and Dissemination). Efficacy and safety comparison of rapid-acting insulin aspart and regular human insulin in the treatment of type 1 and type 2 diabetes mellitus: a systematic review. 2011. PMID 21333580. Read the source