Improved glycaemic control with a fixed-ratio combination of basal insulin and a GLP-1 RA in T2DM
For patients with type 2 diabetes mellitus (T2DM) whose glucose levels remain uncontrolled despite basal insulin therapy, guidelines recommend intensifying treatment with the addition of a rapid-acting prandial insulin or a glucagon-like peptide 1 receptor agonist (GLP-1 RA). At the Endocrinology, Diabetes and Metabolism Hong Kong (EDMHK) 3rd Annual Meeting, Dr Wing-Sun Chow, Specialist in Endocrinology, Diabetes and Metabolism in Hong Kong, discussed the role of a fixed-ratio combination (FRC) of insulin glargine (IGlar) and the GLP-1 RA lixisenatide (IGlarLixi) in improving glycaemic control in patients with previously uncontrolled T2DM.
Unmet needs in PPG control and obstacles to treatment intensification
Many patients with T2DM have poor glycaemic control despite treatment with multiple oral antidiabetic drugs (OADs) or insulin therapy. These patients are at increased risk of cardiovascular disease (CVD) or other complications and can remain in poor glycaemic control for several years before treatment intensification. [Diabetes Care 2013;36:3411-3417]
“Our aim in patients with T2DM is to maintain HbA1c levels at 6.5–7.5 percent to reduce the risk of complications,” said Chow. “However, a substantial proportion of these patients remain uncontrolled due to residual hyperglycaemia, in which they are unable to meet HbA1c targets despite achieving fasting plasma glucose [FPG] control.”
Globally, 24–54 percent of patients with T2DM have residual hyperglycaemia, suggesting a significant unmet need in postprandial glucose (PPG) control. [Diabetes Metab Res Rev 2017;33:e2858] In one study, PPG excursions were found to be the predominant contributor to the residual hyperglycaemia seen in fairly controlled patients. [Diabetes Care 2003;26:881-885]
Additionally, treatment intensification is often complicated by factors such as complex dose titration systems, fear of weight gain and hypoglycaemia, and poor adherence to treatment, including dose omissions. [Curr Med Res Opin 2011;27(Suppl 3):13-20] Poor compliance can greatly affect treatment efficacy and has been linked to higher HbA1c levels as well as increased risks of hospitalization and all-cause mortality. [Am J Manag Care 2008;14:71-75; Arch Intern Med 2006;166:1836-1841]
Basal insulin plus GLP-1 RA: Complementary approach to HbA1c control
The combination of basal insulin plus GLP-1 RA helps address multiple physiologic defects associated with T2DM and offers the benefit of targeting PPG excursions. Basal insulin helps maintain glycaemic control by stimulating peripheral glucose uptake and inhibiting hepatic glucose production. [Diabetes Metab Syndr Obes 2016; 9:355-369] In contrast, GLP-1 RAs control blood glucose through multiple mechanisms that include enhancing glucose-dependent insulin secretion from pancreatic β-cells, suppressing elevated glucagon secretion, overcoming β-cell incretin resistance, reducing gastric emptying and absorption of postprandial glucose, thereby inducing satiety, which minimizes weight gain. [Diabetes Obes Metab 2013;15:485-502]
“While basal insulin acts to improve FPG and nocturnal hypoglycaemia, short-acting GLP-1 RAs can significantly reduce PPG excursions without additional risk of hypoglycaemia through delaying gastric emptying and reducing glucagon release,” explained Chow.
Treatment intensification with IGlarLixi FRC
The efficacy of the once-daily, titratable, IGlarLixi FRC in uncontrolled T2DM patients was assessed in the phase III, randomized, open-label, parallel-group Lixilan-L study. In the trial, 736 patients with HbA1c of 7–10 percent and mean fasting self-measured plasma glucose (SMPG) of ≤7.8 mmol/L, who had been receiving basal insulin at a stable dose of 15–40 U/day for >3 months, were randomized to receive once-daily IGlarLixi or IGlar with or without metformin for 30 weeks. [Diabetes Care 2016;39:1972-1980]
After 30 weeks of treatment, a significant reduction in mean HbA1c level from baseline was observed in patients treated with IGlarLixi vs IGlar (mean, 1.1 percent vs 0.6 percent; difference, -0.5; 95 percent confidence interval [CI], -0.6 to -0.4; p<0.0001). The final mean HbA1c was 6.9 percent in the IGlarLixi group and 7.5 percent in the IGlar group after 30 weeks of treatment. [Diabetes Care 2016;39:1972-1980] Notably, the improvement in HbA1c with IGlarLixi was seen irrespective of baseline HbA1c levels. Consistent HbA1c benefit of IGlarLixi vs IGlar was demonstrated in post-hoc analysis across all patient subgroups, stratified by baseline HbA1c levels (≤8 percent, >8 percent and ≤9 percent, and >9 percent; p<0.0001 for all). (Figure 1) [Diabetes Ther 2018;9:373-382]
“The ease of use of a single, daily IGlarLixi injection may address some of the potential adherence issues associated with treatment intensification in patients with poorly controlled, basal-insulin–treated T2DM, and may lead to greater compliance and satisfaction,” said Chow. “The Lixilan-L study shows that IGlarLixi offers significantly improved glycaemic control over IGlar in these patients.”
In patients who received IGlarLixi, 54.9 percent and 33.9 percent achieved target HbA1c levels of <7.0 percent and <6.5 percent, compared with 29.6 percent and 14.2 percent of patients receiving IGlar, respectively (difference: 25.5 percent with HbA1c <7.0 percent; 95 percent CI, 18.9 to 32.1; p<0.0001 and 19.8 percent with HbA1c <6.5 percent; 95 percent CI, 13.9 to 25.6; p<0.0001). [Diabetes Care 2016;39:1972-1980]
Furthermore, PPG control was significantly improved in patients receiving IGlarLixi vs IGlar, based on a 2-hour glucose excursion test from baseline to week 30 (-3.9 mmol/L vs -0.5 mmol/L; 95 percent CI, -3.9 to -2.9; p<0.0001) and on a 2-hour PPG test (-4.7 mmol/L vs -1.4 mmol/L; 95 percent CI, -3.9 to -2.8). (Figure 2) [Diabetes Care 2016;39:1972-1980]
Notably, the improvements in glycaemic control with IGlarLixi were associated with significant improvements in body weight. After 30 weeks of treatment in Lixilan-L, patients who received IGlarLixi demonstrated a 0.7 kg reduction in weight vs a 0.7 kg increase in weight in those who received IGlar (difference, -1.4 kg; 95 percent CI, -1.8 to -0.9; p<0.0001). (Figure 3) [Diabetes Care 2016;39:1972-1980]
The IGlarLixi FRC has a role in the treatment of patients with poorly controlled, basal insulin-treated T2DM, with demonstrated efficacy in improving glycaemic control and reducing weight gain, without the additional risk of hypoglycaemia whilst having the convenience of once daily injection. Its ease of use and complementary mechanisms of action help address the multiple physiologic defects associated with T2DM and support combining a titratable, FRC of basal insulin with GLP-1 RA when treatment intensification is warranted.