Insulin Glargine: A Long-Acting Insulin Analogue
Insulin glargine, sold under the brand names Lantus and Basaglar among others, is a long-acting, basal insulin analogue used to treat diabetes mellitus. Insulin glargine was developed to provide enhanced glycemic control over 24 hours with just one injection per day. Compared to human insulin, insulin glargine has a slower time of onset, a smoother and more prolonged time-action profile without pronounced peaks. In this article, we will discuss in detail about insulin glargine, how it works, its efficacy and safety profile.
History and Development
Insulin glargine was developed by Sanofi through genetic engineering techniques to modify the amino acid sequence of human insulin. The goal was to develop an insulin analogue with a slower absorption rate from the subcutaneous fat tissue. Two arginine residues were added to the C-terminus of the B-chain of insulin which causes the molecule to be insoluble at physiological pH levels. This property allows insulin glargine to precipitate after injection, forming a subcutaneous depot from which it is gradually absorbed into the circulation. The first-generation formulation was approved in 2000 and the current improved formulation was launched in 2015 which has demonstrated better glucose lowering effects and lesser day-to-day variability.
Mechanism of Action
Unlike short-acting human insulin, insulin glargine has a slower onset of action starting around 1-2 hours and lasting up to 24 hours after subcutaneous administration without any pronounced peak. This allows it to maintain basal or background insulin levels needed by the body constantly throughout the day and night. The mechanism by which it achieves a prolonged duration of action is due to its low solubility at physiological pH levels of 7.4. Once injected, it precipitates forming a subcutaneous depot from where it slowly dissolves and gets absorbed into systemic circulation. The stable hexamer form dissociates into active monomers only as concentrations in circulation rise. This unique crystallization process results in a protracted and steady absorption profile resembling basal insulin secretion.
Efficacy in Glycemic Control
Numerous clinical trials have demonstrated insulin glargine to be at least as effective as NPH human insulin in achieving glycemic control as measured by HbA1c levels. Some key trials are discussed below:
- In a 26-week trial (n=1043), insulin glargine once daily was found to be non-inferior to NPH insulin thrice daily with similar HbA1c reductions from baseline of 1.4% vs 1.5% respectively with no significant differences in hypoglycemia rates.
- Another 30-week trial (n=1627) found significantly lower rates of confirmed (3.1 vs 3.9 events/patient-year) and nocturnal hypoglycemia (1.1 vs 1.6 events/patient-year) with insulin glargine compared to NPH insulin while maintaining similar HbA1c lowering of 0.3%.
- A 3-year trial (n=1518 patients) concluded that insulin glargine provided more successful glycemic control (HbA1c ≤7%) with lower rates of hypoglycemia compared to NPH insulin and standardized diabetes management.
- A meta-analysis of 26 randomized trials involving over 8000 patients found insulin glargine to be at least as effective as NPH insulin in terms of glycemic control and risk reduction of any hypoglycemia while associated with a lower risk of nocturnal hypoglycemia.
Safety Profile
Insulin glargine has an excellent safety profile since its launch in 2000. Some of the key points regarding its safety are:
- Hypoglycemia: Several studies demonstrated a lower risk of hypoglycemia especially nocturnal hypoglycemia compared to NPH insulin. This may be attributed to a more steady and prolonged absorption profile without pronounced peaks.
- Allergic reactions: Local or generalized allergic reactions may rarely occur with insulin glargine but the risk is similar to that of human insulin.
- Malignancy: Some initial observational studies raised concerns about a potential increased cancer risk which could not be definitively confirmed or ruled out in subsequent trials and meta-analyses. The weight of current evidence indicates no significant increase in cancer risk.
- Retinopathy and other complications: Long-term trials have not demonstrated any increased risk of retinopathy and other diabetes complications compared to human insulin.
- Pregnancy and lactation: Insulin glargine can be used in pregnancy and lactation due to low placental transfer. However, careful glycemic control and fetal monitoring are recommended.
In summary, insulin glargine provides superior glycemic control compared to intermediate-acting human insulin with significant reduction in hypoglycemia especially nocturnal hypoglycemia. It acts as a true basal insulin through a gradual absorption process mimicking normal physiology. Over two decades of clinical experience including large outcomes trials have established its safety and efficacy as a preferred basal insulin especially for once daily administration in type 1 and type 2 diabetes. Insulin glargine continues to serve as the gold standard long-acting insulin and first-line treatment option for patients requiring basal insulin therapy.
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