Insulin glargine
glargine, HOE 901, Gly(A21), Arg(B31), Arg(B32) human insulin, insulin glargine U100, insulin glargine U300
Insulin glargine is a long-acting recombinant insulin analogue, licensed since 2000, that provides background (basal) insulin cover for roughly a day from a single injection. It works by being soluble in an acidic solution but precipitating into a microprecipitate depot when injected under the skin at physiological pH, from which insulin redissolves slowly. It is one of the most extensively studied medicines in diabetes, with hundreds of randomised trials and a 12,537-participant cardiovascular outcome trial behind it.
Mechanism
Insulin glargine is human insulin with two engineered changes: asparagine at position A21 is replaced by glycine, and two arginine residues are added to the C-terminus of the B chain at positions B31 and B32. The added positive charge shifts the isoelectric point from about 5.4 to about 6.7, close to physiological pH. The product is therefore formulated as a clear solution at pH 4, where it is fully soluble, and precipitates into an amorphous microprecipitate immediately on injection into subcutaneous tissue at pH 7.4. Slow redissolution of that depot, rather than any change in receptor pharmacology, is what produces the flat, protracted absorption profile. The A21 glycine substitution is a stability measure: asparagine at A21 is prone to acid-catalysed deamidation, and glycine removes that degradation route in the acidic formulation.
Once absorbed, glargine is rapidly processed at the B-chain C-terminus by carboxypeptidase-like activity in subcutaneous tissue into two metabolites: M1 (21A-Gly-human insulin) and, to a much lesser extent, M2 (21A-Gly-des-30B-Thr-human insulin). M1 is the predominant species in the circulation and is essentially the molecule responsible for the clinical effect. Both parent and metabolites act on the insulin receptor in the ordinary way: autophosphorylation of the β-subunit tyrosine kinase, recruitment of IRS-1/2, activation of PI3K-AKT signalling, GLUT4 translocation in muscle and adipose tissue, and suppression of hepatic gluconeogenesis and glycogenolysis. This distinction matters historically: the intact glargine molecule has roughly six- to eightfold higher affinity for the IGF-1 receptor than human insulin in vitro, which drove a mitogenicity scare in the late 2000s, but M1, the form actually circulating, has IGF-1 receptor affinity comparable to human insulin. A 300 U/mL concentrated formulation of the same molecule produces a smaller, more compact depot with a lower surface-area-to-volume ratio, and therefore an even slower, flatter release lasting beyond 24 hours.
What the research shows
The core finding across two and a half decades of trials is consistent and narrower than marketing has often implied. Against isophane (NPH) insulin, glargine delivers equivalent HbA1c with roughly a quarter fewer episodes of nocturnal hypoglycaemia, and a flatter profile that permits once-daily dosing in most people. It does not improve HbA1c beyond what a well-titrated isophane regimen achieves, and the Cochrane review emphasised that no trial has demonstrated a reduction in diabetes complications, mortality or quality of life attributable to the analogue rather than to glycaemic control itself. The 2018 Lipska cohort found no reduction in hypoglycaemia-related emergency attendances in ordinary clinical practice, where structured titration support is less available than in trials.
The most important negative results deserve equal weight. ORIGIN showed that six years of basal glargine in people with dysglycaemia and cardiovascular risk produced no cardiovascular benefit whatsoever, at the cost of a large excess of severe hypoglycaemia and about 1.6 kg more weight gain than standard care. It did, however, definitively resolve the cancer question raised by observational studies published in Diabetologia in 2009: cancer incidence was identical between arms, and subsequent mechanistic work established that the circulating M1 metabolite, not the intact molecule with its higher IGF-1 receptor affinity, is what tissues are actually exposed to. Head-to-head against insulin degludec, glargine U100 shows a modestly higher rate of nocturnal hypoglycaemia; against the 300 units/mL concentrated formulation of glargine itself, the more concentrated product gives a flatter profile and somewhat less nocturnal hypoglycaemia at similar HbA1c. Glargine remains the standard comparator arm in virtually every new basal insulin trial, which is itself a statement about the strength of its evidence base.
Evidence assessment
High-quality evidence
Licensed by the FDA and in the European Union since 2000 on the basis of multiple adequately powered randomised controlled trials, supported by a dedicated 12,537-participant cardiovascular and cancer outcome trial (ORIGIN) with median 6.2 years of follow-up, and by a Cochrane systematic review. The evidence base is genuinely strong, though it is worth noting that what it strongly establishes is a modest reduction in nocturnal hypoglycaemia at equivalent HbA1c, not superior glycaemic control or better long-term outcomes than isophane insulin.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients Preclinical only
Both insulins achieved a mean HbA1c of about 6.96%, with roughly 60% of participants reaching HbA1c below 7%. The difference was in safety, not efficacy: more participants reached target without documented nocturnal hypoglycaemia on glargine (about 33% versus 27% on isophane insulin), and rates of nocturnal hypoglycaemia were about a quarter lower with glargine.
Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes Preclinical only
Once-daily glargine produced lower fasting plasma glucose than isophane insulin with similar HbA1c, and fewer episodes of symptomatic and nocturnal hypoglycaemia. This pair of trials formed a substantial part of the original registration dossier.
Basal insulin and cardiovascular and other outcomes in dysglycemia Preclinical only
Neither co-primary cardiovascular composite differed from standard care (hazard ratios 1.02 and 1.04). Cancer incidence was identical (hazard ratio 1.00), which laid to rest the 2009 observational mitogenicity signal. Severe hypoglycaemia was substantially more common with glargine (1.00 versus 0.31 per 100 person-years) and body weight rose by about 1.6 kg more than with standard care. This is the single most important negative result for glargine: long-term basal insulin in early dysglycaemia does not improve cardiovascular outcomes.
Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus Preclinical only
No clinically relevant difference in HbA1c between long-acting analogues and isophane insulin. Modest reductions in symptomatic and nocturnal hypoglycaemia were found, but the reviewers concluded there was no evidence at all on patient-relevant long-term outcomes such as mortality, morbidity or quality of life.
Association of Initiation of Basal Insulin Analogs vs Neutral Protamine Hagedorn Insulin With Hypoglycemia-Related Emergency Department Visits or Hospital Admissions and With Glycemic Control in Patients With Type 2 Diabetes Preclinical only
Hypoglycaemia-related emergency visits were 11.9 per 1,000 person-years with analogues versus 8.8 with isophane insulin; after matching, the adjusted hazard ratio was 1.16 (95% CI 0.71-1.78), no reduction in serious hypoglycaemia. HbA1c change was comparable. A genuinely uncomfortable finding for the analogue-superiority argument, though observational and subject to confounding by indication.
Safety
The dose-limiting adverse effect is hypoglycaemia, which can be severe and life-threatening. Risk rises with tighter glycaemic targets, renal or hepatic impairment (both reduce insulin clearance), missed meals, alcohol, exercise, weight loss, and concurrent sulfonylureas. Repeated hypoglycaemia causes hypoglycaemia unawareness, which is a specific hazard for driving; in the UK, DVLA rules apply to anyone treated with insulin. Weight gain of one to three kilograms on initiation is typical. Hypokalaemia occurs because insulin drives potassium intracellularly, and is clinically relevant in acute settings. Injection-site lipohypertrophy from failure to rotate sites is common and causes erratic absorption. The acidic pH 4 formulation causes stinging in some people. Rare effects include true systemic insulin allergy, anti-insulin antibodies, injection-site lipoatrophy, peripheral oedema and transient refractive changes on rapid glycaemic improvement. Combining insulin with a thiazolidinedione increases fluid retention and heart-failure risk. Glargine must not be mixed in a syringe with any other insulin. Mixing destroys the precipitation behaviour that produces its duration. Insulin is a high-alert medicine: the existence of 100, 200, 300 and 500 units/mL products has produced tenfold dosing errors, and concentration must always be confirmed. Non-medical use by bodybuilders and others without diabetes has caused deaths from profound hypoglycaemia and hypoglycaemic brain injury; there is no safe recreational use of any insulin.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Licensed by the MHRA for type 1 and type 2 diabetes in adults, adolescents and children from 2 years of age (100 units/mL) and in adults (300 units/mL). Prescription-only medicine (POM). Recommended in NICE guidance NG17 (type 1 diabetes) and NG28 (type 2 diabetes) as a basal insulin option, and included on the WHO Model List of Essential Medicines since long-acting insulin analogues were added in 2021. |
| United States | FDA-approved in April 2000 (100 units/mL) as a prescription biologic for type 1 and type 2 diabetes in adults and children; a 300 units/mL formulation was approved in 2015. Since March 2020 insulin glargine has been regulated as a biological product under section 351 of the Public Health Service Act, which opened the pathway for biosimilars; the first interchangeable biosimilar insulin glargine was licensed in July 2021. Prescription-only. |
| WADA (sport) | Prohibited at all times, in and out of competition, for athletes under the WADA Code. Insulins and insulin-mimetics are listed under section S4 (Hormone and Metabolic Modulators). Athletes with diabetes require a Therapeutic Use Exemption. |
Questions
Yes, in the strict sense: it is a 53-residue two-chain polypeptide. It sits at the boundary between what people usually mean by 'peptide' and what is usually called a protein, and it is manufactured as a recombinant biologic rather than by chemical synthesis. It is included in this library because it is one of the reference molecules against which every other engineered peptide hormone is judged.
In 2009 several observational database studies published together in Diabetologia suggested a possible dose-related association with cancer, which was biologically plausible because the intact glargine molecule binds the IGF-1 receptor with roughly six- to eightfold the affinity of human insulin. The concern was largely resolved on two fronts: the ORIGIN randomised trial found identical cancer incidence over 6.2 years (hazard ratio 1.00), and pharmacokinetic work showed that the molecule circulating in the body is the M1 metabolite, whose IGF-1 receptor affinity is comparable to human insulin.
Chemically, glargine is an engineered analogue in a clear acidic solution, whereas isophane insulin is unmodified human insulin crystallised with protamine as a cloudy suspension that must be resuspended before use. Clinically, glargine gives a flatter profile that usually permits once-daily dosing and produces roughly a quarter fewer nocturnal hypoglycaemic episodes at the same HbA1c. It does not achieve better HbA1c, and no trial has shown it reduces long-term complications relative to isophane insulin.
Biosimilars are approved on the basis of demonstrated analytical, pharmacokinetic, pharmacodynamic and clinical similarity to the reference product. Several have been licensed in the EU since 2014 and in the US since 2016, with the first product designated interchangeable in the US in July 2021. Regulators regard the licensed biosimilars as therapeutically equivalent; switching is nonetheless a clinical decision for a prescriber, since the delivery devices differ.
They contain the same molecule. Concentrating it threefold produces a smaller injected volume and therefore a more compact subcutaneous depot with less surface area relative to its volume, so redissolution is slower still. The result is a flatter profile lasting beyond 24 hours and modestly less nocturnal hypoglycaemia. The two are not interchangeable unit-for-unit, and confusing them is a recognised source of serious dosing error.