Insulin Glargine

What it is

Insulin glargine is a manufactured long-acting form of insulin given by injection under the skin. The US label (revised 06/2022) says it is indicated to improve blood sugar control in adults and children with diabetes, and is not for treating diabetic ketoacidosis.

What the research says

It lowers blood sugar. Compared with older NPH insulin, Cochrane reviews found similar HbA1c with somewhat less nocturnal or confirmed low blood sugar in type 2 diabetes, but evidence on death and complications was lacking and certainty was low. In the ORIGIN trial (12,537 people), glargine had no effect on heart attacks, strokes or cardiovascular death, and no effect on cancer, but caused more severe low blood sugar and weight gain.

Evidence grade: Well established.

How it works

Drug class: Long-acting basal insulin analogue

Like the body's own insulin, glargine lowers blood sugar by helping muscle and fat take up glucose and by reducing the liver's release of glucose. It is released slowly from under the skin, giving a steady background level. (Source 1)

What it is used for

• Glargine lowers glucose; versus NPH insulin, HbA1c was similar and confirmed and nocturnal hypoglycaemia was lower, but trials were short with low to very low certainty and little data on death or complications. In ORIGIN it did not change cardiovascular outcomes. Evidence: established. (Source 2)
• In the Cochrane review, severe hypoglycaemia was 10.2% with glargine versus 12.5% with NPH, with almost no HbA1c difference (0.02%). Evidence: established. (Source 3)
• In ORIGIN, among 1,456 participants without diabetes at baseline, new diabetes 3 months after stopping was 30% versus 35% (OR 0.80, P=0.05), at the cost of more hypoglycaemia and weight gain. Evidence: limited. (Source 4)
• ORIGIN found no cardiovascular benefit over 6.2 years (HR 1.02). Evidence: not-supported. (Source 4)

Interactions

• Alcohol (label): Alcohol can either increase or decrease the glucose-lowering effect of insulin, so blood sugar becomes less predictable. (Source 1)
• Beta-blockers, clonidine, guanethidine, reserpine (label): These can mask the warning signs of low blood sugar. (Source 1)
• Thiazolidinediones (pioglitazone, rosiglitazone) (label): Combined with insulin, these can cause fluid retention that may worsen heart failure. (Source 1)

Stopping it

• In ORIGIN, about 3 months after glargine was stopped, new diabetes was found in 30% of people without diabetes at baseline versus 35% on standard care, a small borderline difference. No trial or review on stopping insulin in type 1 diabetes was retrieved in this run. (Source 4)

What goes wrong

In ORIGIN, glargine more than tripled the rate of severe hypoglycaemia compared with standard care. (Source 4)

• Randomized trial, High certainty.
• Size: 12,537.
• Who: Adults with dysglycaemia and cardiovascular risk.
• How long: Median 6.2 years.
• Result: 1.00 vs 0.31 per 100 person-years.
• Funding: not stated in the fetched abstract.

Rates of severe hypoglycemia were 1.00 versus 0.31 per 100 person-years.

In ORIGIN, weight rose on glargine and fell on standard care. (Source 4)

• Randomized trial, High certainty.
• Size: 12,537.
• Who: Adults with dysglycaemia and cardiovascular risk.
• How long: Median 6.2 years.
• Result: Median +1.6 kg vs -0.5 kg.
• Funding: not stated in the fetched abstract.

Median weight increased by 1.6 kg in the insulin-glargine group and fell by 0.5 kg in the standard-care group.

A large German insurance cohort reported a dose-dependent higher cancer risk with glargine than human insulin; this is observational and later randomised data (ORIGIN) did not confirm it. (Source 5)

• Cohort study, Very low certainty.
• Size: 127,031 patients.
• Who: Insulin-treated people with diabetes in German statutory insurance data.
• How long: Mean 1.63 years.
• Result: Adjusted HR 1.09 (1.00 to 1.19) at 10 IU/day, 1.31 (1.20 to 1.42) at 50 IU/day.
• Funding: not stated in the fetched abstract.

After adjusting for dose, a dose-dependent increase in cancer risk was found for treatment with glargine compared with human insulin (p < 0.0001)

The label warns that severe hypoglycaemia can cause seizures and death. (Source 1)

• Official position, Certainty not rated.
• Size: Not applicable.
• Who: Insulin users.
• How long: Not applicable.
• Result: No rate given in this sentence.
• Funding: Label (FDA-approved manufacturer text, revised 06/2022)

Severe hypoglycemia can cause seizures, may be life-threatening or cause death.

What the evidence supports

In ORIGIN, glargine modestly reduced new diabetes diagnosed after therapy stopped in people without diabetes at baseline, at borderline significance. (Source 4)

• Randomized trial, Moderate certainty.
• Size: 1,456 participants without baseline diabetes.
• Who: Adults with impaired fasting glucose or impaired glucose tolerance.
• How long: Median 6.2 years plus about 3 months off therapy.
• Result: 30% vs 35%; OR 0.80 (95% CI 0.64 to 1.00); P=0.05.
• Funding: not stated in the fetched abstract.

New diabetes was diagnosed approximately 3 months after therapy was stopped among 30% versus 35% of 1456 participants without baseline diabetes

What the evidence does not support

In ORIGIN, targeting normal fasting glucose with glargine did not reduce cardiovascular events. (Source 4)

• Randomized trial, High certainty.
• Size: 12,537 people.
• Who: Adults (mean age 63.5) with cardiovascular risk factors plus impaired fasting glucose, impaired glucose tolerance or type 2 diabetes.
• How long: Median 6.2 years.
• Result: 2.94 vs 2.85 per 100 person-years; HR 1.02 (95% CI 0.94 to 1.11); P=0.63.
• Funding: not stated in the fetched abstract (the trial is widely reported as Sanofi-sponsored; not verified in this run)

2.94 and 2.85 per 100 person-years, respectively, for the first coprimary outcome (hazard ratio, 1.02; 95% confidence interval [CI], 0.94 to 1.11; P = 0.63)

In ORIGIN, glargine did not change cancer rates. (Source 4)

• Randomized trial, High certainty.
• Size: 12,537.
• Who: Adults with dysglycaemia and cardiovascular risk.
• How long: Median 6.2 years.
• Result: HR 1.00 (95% CI 0.88 to 1.13); P=0.97.
• Funding: not stated in the fetched abstract.

There was no significant difference in cancers (hazard ratio, 1.00; 95% CI, 0.88 to 1.13; P = 0.97).

In type 2 diabetes, glargine and NPH insulin lowered HbA1c by similar amounts. (Source 2)

• Systematic review, Low certainty.
• Size: 24 RCTs; 3,419 participants on glargine.
• Who: Adults with type 2 diabetes.
• How long: 24 weeks to 5 years.
• Result: HbA1c comparable.
• Funding: not stated in the fetched text.

Changes in HbA1c were comparable for long-acting insulin analogues and NPH insulin.

The Cochrane review found trial data on death, complications and quality of life were insufficient or lacking. (Source 2)

• Systematic review, Low certainty.
• Size: 24 RCTs.
• Who: Adults with type 2 diabetes.
• How long: 24 weeks to 5 years.
• Result: No usable estimate for patient-relevant outcomes.
• Funding: not stated in the fetched text.

Information on patient-relevant outcomes such as death from any cause, diabetes-related complications, health-related quality of life and socioeconomic effects was insufficient or lacking in almost all included trials.

Where the evidence is mixed

In type 2 diabetes, glargine reduced confirmed and nocturnal hypoglycaemia compared with NPH; the reduction in severe hypoglycaemia was uncertain. (Source 2)

• Systematic review, Low certainty.
• Size: 24 RCTs.
• Who: Adults with type 2 diabetes.
• How long: 24 weeks to 5 years.
• Result: Severe hypoglycaemia RR 0.68 (95% CI 0.46 to 1.01)
• Funding: not stated in the fetched text.

Treatment with insulin glargine reduced the incidence of confirmed hypoglycaemia and confirmed nocturnal hypoglycaemia.

In type 1 diabetes, severe hypoglycaemia was 10.2% with glargine versus 12.5% with NPH insulin. (Source 3)

• Systematic review, Moderate certainty.
• Size: 2,350 participants in the glargine vs NPH comparison.
• Who: People with type 1 diabetes.
• How long: Trials of at least 24 weeks.
• Result: 122/1191 vs 145/1159; HbA1c mean difference 0.02%.
• Funding: not stated in the fetched text.

Severe hypoglycaemia was observed in 122/1191 participants (10.2%) in the insulin glargine group compared with 145/1159 participants (12.5%) in the NPH insulin group

Where the research disagrees

Whether insulin glargine raises cancer risk

• Hemkens et al., German insurance cohort (2009), cohort: Our results based on observational data support safety concerns surrounding the mitogenic properties of glargine in diabetic patients. (Source 5)
• ORIGIN trial investigators (2012), rct: When used to target normal fasting plasma glucose levels for more than 6 years, insulin glargine had a neutral effect on cardiovascular outcomes and cancers. (Source 4)

How much

• Reference intake: Dosing is set by the prescriber and individualised. As a position, the US label (06/2022) gives a starting dosage for insulin-naive type 2 diabetes of 0.2 units/kg or up to 10 units once daily. (Source 1)
• Upper limit: No maximum dose is stated in the fetched label text; the label directs individualising dosage by blood glucose monitoring. (Source 1)
• Studied: ORIGIN titrated glargine to a target fasting blood glucose of 95 mg/dL (5.3 mmol/L) or less. (Source 4)

A common belief, and what the research shows

The belief: Insulin glargine causes cancer.

What the research shows: The concern came from an observational cohort. In the randomised ORIGIN trial over 6.2 years, "There was no significant difference in cancers (hazard ratio, 1.00; 95% CI, 0.88 to 1.13; P = 0.97)."

Questions and answers

What is it?

Insulin glargine is a manufactured, long-acting version of insulin injected under the skin (brands include Lantus, Toujeo, Basaglar and Semglee). It is a prescription medicine for diabetes. (Source 1)

What does it do in the body?

It acts like the body's own insulin: it helps muscle and fat take up sugar from the blood and reduces the liver's output of sugar, giving a steady background level of insulin. (Source 1)

Is it good or bad for you?

It is essential for many people with diabetes and lowers blood sugar. In a large trial it did not prevent heart disease and it caused more severe low blood sugar and some weight gain. (Source 4)

How do you get more of it?

Does not apply as a nutrient: glargine is a prescription injection and the dose is individualised by the prescriber based on glucose monitoring. (Source 1)

If it is harmful, what reduces it?

The main harm of too much insulin is low blood sugar (hypoglycaemia), which the label says can be severe and dangerous. Management of an overdose is a medical matter. (Source 1)

Why might someone be low in it or missing it?

Does not apply: glargine is not made by the body. It is prescribed when a person with diabetes needs insulin for glucose control; it is not a treatment for diabetic ketoacidosis. (Source 1)

Which whole foods contain it or feed it?

Does not apply: no food contains insulin glargine. Alcohol is listed on the label among things that can raise or lower its glucose-lowering effect. (Source 1)

What happens if you do not have it?

In people with prediabetes in ORIGIN, those who had been on glargine were slightly less likely to have diabetes 3 months after stopping. For people with type 1 diabetes, who need insulin to live, no stopping study was retrieved in this run. (Source 4)

How can you test for it?

Glargine levels are not measured in routine care; its effect is followed by blood glucose monitoring and HbA1c, which the label uses to guide dosing. (Source 1)

References

1. Sanofi-Aventis / US FDA (Drugs@FDA). LANTUS (insulin glargine injection) - Prescribing Information. 2022. Read the source
2. Cochrane. (Ultra-)long-acting insulin analogues compared with NPH insulin (human isophane insulin) for adults with type 2 diabetes mellitus (Semlitsch T et al., CD005613), plain-language evidence page. 2020. PMID 33166419, DOI 10.1002/14651858.CD005613.pub4. Read the source
3. Cochrane. (Ultra-)long-acting insulin analogues for people with type 1 diabetes mellitus (Hemmingsen B et al., CD013498). 2021. DOI 10.1002/14651858.CD013498.pub2. Read the source
4. New England Journal of Medicine (abstract via Monash University research portal). Basal insulin and cardiovascular and other outcomes in dysglycemia (ORIGIN Trial Investigators). 2012. PMID 22686416, DOI 10.1056/NEJMoa1203858. Read the source
5. Diabetologia (Springer). Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. 2009. PMID 19565214, DOI 10.1007/s00125-009-1418-4. Read the source