Insulin glargine U300 improves glycaemic control with no increase in hypoglycaemia
IGlar U300: A second-generation basal insulin analogue
Second-generation basal insulins are designed to have a protracted time-action profile to facilitate basal glucose control over 24 hours. Difference in time-action profile is achieved through a unique mechanism of action leading to different behaviours in subcutaneous (SC) space and rates of absorption into the circulation. [Adv Ther 2019;36:1018-1030]
IGlar U300 is a different formulation of glargine compared with IGlar U100, whereby the same amount of insulin is delivered in one-third of the volume through a compact depot with a reduced surface area of micro-precipitates, resulting in a slower, more gradual release of insulin monomers into the bloodstream with a smoother pharmacokinetic profile over the 24-hour period. At the same time, the reduced volume of insulin degludec (IDeg) does not affect the multihexamer formation or microprecipitation in the SC space. [Adv Ther 2019;36:1018-1030; Diabetes Metab Syndr Obes 2017;10:273-284; Pharm Res 2012;29:2104-2114]
BRIGHT: IGlar U300 lowers HbA1c without increasing hypoglycaemia
In this multicentre, open-labelled, randomized, active-controlled, two-arm parallel-group, 24-week noninferiority clinical trial, insulin-naïve patients with uncontrolled T2DM (duration of T2DM, 10.5–10.7 years; mean HbA1c, 8.1–8.6 percent) were randomized (1:1) to evening dosing with IGlar U300 (n=466) or IDeg U100 (n=463) (starting doses, as per labelling, 0.2 units/kg and 10 units, respectively), titrated to fasting self-monitored plasma glucose (SMPG) of 80–100 mg/dL . Patient were stratified by HbA1c level and sulphonylurea (SU) or glinide use at screening. [Diabetes Care 2018;41:2147-2154]
The first 12 weeks of treatment constituted the ‘active’ titration period with the aim of target achievement within 8–12 weeks.
At week 24, HbA1c improvements from baseline were comparable between the IGlar U300 and IDeg U100 groups (8.7 percent to 7.0 percent vs 8.6 percent to 7.0 percent, respectively), with a least squares (LS) mean difference of -0.05 percent (95 percent confidence interval [CI], -0.15 percent to 0.05 percent), demonstrating noninferiority of IGlar U300 vs IDeg U100 (p<0.0001) for the primary endpoint. (Figure 1) [Diabetes Care 2018;41:2147-2154]
“IGlar U300 and IDeg U100 were also found to be very similar glycaemically. The small difference between the two treatment arms was maintained in terms of fasting plasma glucose [FPG] [LS mean difference, 0.43 mmol/L; 95 percent CI, 0.15 to 0.70] and, more importantly, fasting SMPG [LS mean difference, 0.06 mmol/L; 95 percent CI, -0.11 to 0.23], with the bulk of decline in glucose level occurring in the first 12 weeks,” commented Cheng.
While the incidence and event rates of hypoglycaemia were similar between IGlar U300 and IDeg U100 during the 24-week treatment period, IGlar U300 was associated with a lower incidence and lower rates of anytime (24-hour) confirmed hypoglycaemia (for both ≤70 mg/dL and <54 mg/dL thresholds) during the titration period (0–12 weeks). (Figure 2) No difference was found in the incidence of hypoglycaemia between IGlar U300 and IDeg U100 regardless of SU or glinide usage. However, a higher tendency for hypoglycaemia was noted in patients who used SUs or glinides at screening. Furthermore, IGlar U300 was comparable to IDeg U100 in the incidence and event rates of nocturnal (00:00-06:00 hour) hypoglycaemia across all study periods. [Diabetes Care 2018;41:2147-2154]
A difference of 0.11 U/kg in mean daily insulin doses between IGlar U300 and IDeg U100 was seen at 24 weeks. The mean dose increase from baseline was 0.36 U/kg for IGlar U 300 and 0.31 U/kg for IDeg U100. [Diabetes Care 2018;41:2147-2154]
“Therefore, in a 70 kg patient, the dose difference is about 7 units. That difference is not a clinical concern, and the BRIGHT study showed that it did not translate into a change in body weight,” said Cheng.
“Results of the BRIGHT study showed that both treatments were excellent in lowering HbA1c, especially when titrated effectively in a timely manner. It also demonstrated that the treatments were very similar in terms of rates of hypoglycaemia, with the only difference being anytime [24-hour] hypoglycaemia in the titration phase, which favoured IGlar U300,” Cheng continued.
“It is important to minimize the risk of hypoglycaemia in DM treatment. Research showed that patients who experienced hypoglycaemia within 6 months of basal insulin initiation were more likely to discontinue treatment,” she emphasized. [Adv Ther 2017;34:2083-2092]
A post-hoc analysis showed that IGlar U300 provided greater reduction in HbA1c at week 24 vs IDeg U100 in patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 (LS mean difference, -0.43; 95 percent; -0.74 to -0.12), with no increase in risk of anytime hypoglycaemia (rate ratio, 0.93; 95 percent CI, 0.56 to 1.54). (Figure 3) [Haluzik M, et al, ADA 2019, abstract 146-OR]
CONCLUDE: IGar U300 vs IDeg U200
Another head-to-head study compared IGlar U300 with IDeg U200 in insulin-experienced T2DM patients at risk of developing hypoglycaemia, with a planned treatment duration of 52 weeks. However, the glycaemic data collection system was found to be erroneous during the trial, leading to inconsistency between central laboratory results and patient-reported SMBG values. As a result, patients were given properly functioning BG meters, and the trial protocol was amended to include a new maintenance period (36 weeks), extending the total treatment duration to 88 weeks. [J Diabetes Sci Technol 2019;13:498-506]
“The 16-week titration period had already been completed by the time the errors with the original glycaemic data collection system was figured out,” pointed out Cheng.
The primary endpoint of the number of severe or BG-confirmed symptomatic hypoglycaemia episodes during the maintenance period (36 weeks, tested for superiority) was not met. [Philis-Tsikmas A, et al, EASD 2019, abstract S#38.2]
Translating science into practice
“Based on the results of BRIGHT, there will be a preference for IGlar U300 in patients initiating basal insulin and in those who experience hypoglycaemia with other types of basal insulin. Since IGlar U300 is injected once daily, it would be suitable for those currently on twice-daily basal insulin who would like to reduce the number of injections. It is also suitable for those on a higher dosage of insulin who prefer a smaller volume of injection,” suggested Cheng.
Glycaemic target achievement can be improved by empowering DM patients to self-titrate IGlar U300 effectively, or by switching to IGlar U300, without increasing hypoglycaemia. [Diabetes 2018, doi: 10.2337/db18-1026-P] “In fact, a study in Canada supports the local practice in advising patients to increase their insulin dosage by 1 unit/day until the FPG target is achieved. This was shown to be as effective as weekly titration,’ said Cheng. [Can J Diabetes 2017:41:478-484] “It is also very important to avoid hypoglycaemia during the early phase of insulin therapy,” she added.