Insulin Glargin U300 (Toujeo)

Description

Insulin Glargine U300 (brand name Toujeo) is a long-acting basal insulin analogue. The molecule itself is identical to the insulin glargine that has been in clinical use for years: asparagine at position A21 is replaced by glycine. Two additional arginine residues are attached at the end of the B chain. These changes shift the isoelectric point towards neutral pH. The solution is therefore clear in the acidic milieu of the cartridge but precipitates as a fine microprecipitate in neutral tissue after subcutaneous injection. The active substance then dissolves out of that depot slowly and over many hours. At the receptor, glargine acts like endogenous insulin: glucose uptake into muscle and fat cells, suppression of hepatic glucose production, inhibition of lipolysis.

The difference to U100 is not the substance, it is the concentration. U300 contains 300 units per millilitre instead of 100. The same number of units therefore sits in one third of the volume. The depot forming under the skin is smaller and has a markedly lower surface area relative to its volume. Because dissolution of the microprecipitate happens across that surface, the active substance is released more slowly and more evenly. A physical property of the formulation thus turns into a pharmacokinetic effect.

The pharmacokinetic profile is well characterised. Becker et al. (2015) compared U300 against U100 in a euglycemic clamp over 36 hours in people with type 1 diabetes at steady state. Insulin concentrations and glucose infusion rates were more constant under U300 and more evenly distributed across 24 hours, visible in the roughly three hours later time to reach half of the area under the curve. Tight blood glucose control lasted a median of about 30 hours under U300, some five hours longer than under U100. There is no pronounced peak. Total duration extends to up to 36 hours. Steady state is only reached after about three to four days of daily administration, which means the full consequence of a dose change only shows up with several days of delay. Relative bioavailability is somewhat lower than with U100: the EDITION studies needed roughly ten percent more units for the same blood glucose control.

The EDITION clinical programme mapped this profile in large randomised comparisons. In EDITION 1 (Riddle et al. 2014, 807 participants with type 2 diabetes on basal and mealtime insulin) the reduction in long-term blood glucose was equivalent between U300 and U100, while fewer participants reported at least one confirmed or severe nocturnal hypoglycemic event between week 9 and month 6 (36 versus 46 percent). EDITION 2 (Yki-Järvinen et al. 2014, 811 participants on basal insulin plus oral antidiabetic drugs) showed the same pattern. The patient-level meta-analysis by Ritzel et al. (2015) across EDITION 1 to 3 pooled 2496 people: identical blood glucose control, with a 31 percent lower rate of nocturnal and a 14 percent lower rate of any-time confirmed or severe hypoglycemia over six months, plus slightly less weight gain. In EDITION 4 (Home et al. 2015) in type 1 diabetes, control was likewise equivalent, with fewer nocturnal events in the first eight weeks and independent of whether the injection was given in the morning or the evening.

In a research context one point belongs first and stated plainly. U300 means 300 units per millilitre. An ordinary insulin syringe is calibrated for U100: the mark labelled 20 there corresponds to 0.2 ml of a 100-unit solution, that is 20 units. If someone draws a U300 solution to that same mark with that same syringe, 60 units sit in the barrel. That is a threefold overdose that looks visually correct. With a long-acting insulin it cannot be taken back for many hours. The pen is built for exactly this problem: its counter displays units and delivers one third of the volume per unit. So without exception: do not transfer into a syringe, do not dilute, do not mix with other insulins, do not confuse with U100 products. On top of that comes the point that holds for every insulin: the dose calculations of diabetes therapy replace something missing there, whereas with an intact pancreas they land on top with nothing to offset them.

You can order Insulin Glargine U300 as a solution for subcutaneous injection at a concentration of 300 IU per ml, in the 1.5ml size containing 450 IU per unit.

This information is for research and educational purposes only. No medical advice.

Risks & Safety

Insulin Glargine U300 is a clinically approved basal insulin with a very well studied action profile. The risk does not come from unknown side effects, it comes from the main effect: the substance lowers blood glucose reliably and dose-proportionally, it does not stop once a safe value is reached. With a duration of up to 36 hours it does so for an extremely long time. Together with the triple concentration, that is the reason for Risk Tier 3.

Documented in clinical studies and in the medication safety literature:

• Confusing U300 with U100: the central, substance-specific error. An insulin syringe calibrated for U100 misreads a U300 solution by a factor of three. Whoever draws to the 20 mark has 60 units. The error is not visually detectable because the scale looks correct. Administration must therefore happen exclusively via the matching pen, whose mechanism delivers one third of the volume per displayed unit. Transferring into a syringe, diluting or mixing with other insulins is a dosing error in every variant.
• Hypoglycemia: the dose-limiting risk of every insulin. Early signs are trembling, sweating, palpitations, ravenous hunger and nervousness, followed by impaired concentration, slurred speech, confusion and aggressive or slowed behaviour. With a further drop come seizure, unconsciousness and death. Cognitive impairment sets in precisely when independent corrective action would be needed. Anyone already confused can as a rule no longer help themselves.
• Long duration as a risk in its own right: unlike a rapid-acting insulin, an excessive basal dose has not worn off after a few hours. It keeps acting for up to 36 hours. A single dose of fast carbohydrates does not cover that window. Hypoglycemia can recur after an initial improvement. For the same reason the full effect of a dose change only appears after three to four days, once steady state is reached.
• No correction without preparation: fast-acting carbohydrates (glucose tablets, juice, sugary drinks) must be within reach before administration, not in a cupboard. Fat- or protein-containing food acts too slowly.
• Never alone, never without measurement: without a blood glucose meter there is no objective feedback on the current value. Subjective impression is unreliable while glucose is falling. Without a second person present who can spot clouding consciousness and get help, the last safeguard is missing. Nocturnal hypoglycemia is particularly relevant with a basal insulin because it can pass unnoticed during sleep. That exact event was the main safety endpoint of the EDITION studies.
• Potassium shift: insulin moves potassium from the extracellular space into cells. Serum potassium falls as a result without total body content changing. Marked hypokalemia can trigger cardiac arrhythmias. That risk is independent of blood glucose: carbohydrates alone do not correct it.
• Interaction with alcohol and physical exertion: alcohol suppresses gluconeogenesis in the liver and thereby disables exactly the mechanism the body uses to catch a hypoglycemia on its own. Muscle work additionally increases insulin-independent glucose uptake. Both amplify and prolong the glucose-lowering effect considerably and in a way that is hard to predict.
• Further documented effects: injection site reactions, lipohypertrophy with repeated injection into the same region and the unpredictable absorption that causes, sodium and water retention with edema at the start of use, weight change and, rarely, allergic reactions. In the EDITION studies weight gain was somewhat lower under U300 than under U100.

This classification does not replace medical advice. Risk and responsibility for any actual use lie entirely with the buyer. If severe hypoglycemia is suspected, particularly with confusion or clouded consciousness, calling emergency services is the only correct response.

Studies

• New insulin glargine 300 Units/mL provides a more even activity profile and prolonged glycemic control at steady state compared with insulin glargine 100 Units/mL - Diabetes Care 2015, Becker et al: euglycemic clamp over 36 hours at steady state, more even activity profile and tight blood glucose control for a median of about 30 hours.
• New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 2 diabetes using basal and mealtime insulin (EDITION 1) - Diabetes Care 2014, Riddle et al: 807 participants over six months, equivalent blood glucose control with fewer nocturnal hypoglycemic events (36 versus 46 percent).
• New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 2 diabetes using oral agents and basal insulin (EDITION 2) - Diabetes Care 2014, Yki-Järvinen et al: 811 participants, identical reduction in long-term glucose at a roughly ten percent higher unit dose and fewer nocturnal events.
• Patient-level meta-analysis of the EDITION 1, 2 and 3 studies: glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus glargine 100 U/ml in people with type 2 diabetes - Diabetes, Obesity and Metabolism 2015, Ritzel et al: pooled analysis across 2496 people, 31 percent lower nocturnal and 14 percent lower any-time hypoglycemia rate.
• New Insulin Glargine 300 Units/mL Versus Glargine 100 Units/mL in People With Type 1 Diabetes (EDITION 4) - Diabetes Care 2015, Home et al: 549 participants with type 1 diabetes, equivalent control independent of injection time, fewer nocturnal events in the first eight weeks.