Rationale for a titratable fixed-ratio co-formulation of a basal insulin analog and a glucagon-like peptide 1 receptor agonist in patients with type 2 diabetes

Abstract

Objective: Achieving and maintaining recommended glycemic targets, including those for glycated hemoglobin A1c (A1C), is key to improving outcomes in patients with type 2 diabetes (T2D). As fasting plasma glucose and postprandial glucose contribute to overall A1C, targeting both is essential for sustaining glycemic control. Methods: This review examines the complementary mechanisms of action of glucagon-like peptide 1 (GLP-1) receptor agonists and basal insulin; they both enhance glucose-stimulated insulin release and suppress glucagon secretion. GLP-1 receptor agonists also slow gastric emptying and increase satiety. Results: Adding a GLP-1 receptor agonist to therapy with a basal insulin analog has been associated with improved overall glycemic control, with comparable risk of hypoglycemia and no weight gain. Titratable fixed-ratio co-formulations of basal insulin and a GLP-1 receptor agonist have been shown to improve glycemic control, with less complex dosing schedules, possibly increasing treatment adherence. The slow titration of fixed-ratio co-formulations has been shown to reduce the occurrence and severity of gastrointestinal adverse events associated with the use of a separate GLP-1 receptor agonist. Titratable fixed-ratio co-formulations also mitigate insulin-associated weight gain, and show a comparable risk of hypoglycemia to basal insulin use alone. Conclusions: The efficacy and safety of titratable fixed-ratio co-formulations have been demonstrated for insulin degludec/liraglutide and insulin glargine/lixisenatide in the DUAL and LixiLan trials, respectively, in both insulin-naive and -experienced patients. Titratable fixed-ratio co-formulations represent an attractive treatment option for many patients with T2D. ARTICLE HISTORY

Advancing Therapy in Suboptimally Controlled Basal Insulin–Treated Type 2 Diabetes: Clinical Outcomes With iGlarLixi Versus Premix BIAsp 30 in the SoliMix Randomized Controlled Trial

“…FRCs combine the complementary mechanisms of action of two individual components in one formulation; basal insulin primarily reduces fasting plasma glucose (FPG) while the GLP-1 RA targets post-prandial glucose (PPG). Overall, GLP-1 RAs act through a glucose-dependent mechanism by which they stimulate insulin secretion while preventing Premix RCT primary manuscript peer review 08 June 2021 glucagon increase (12). Short-acting GLP-1 RAs, specifically target PPG with a predominant gastric emptying effect, while long-acting GLP-1 RAs, exert their effect predominantly through pancreatic functions, resulting in a lesser impact on PPG but larger overall reductions in FPG (12).…”

“…Overall, GLP-1 RAs act through a glucose-dependent mechanism by which they stimulate insulin secretion while preventing Premix RCT primary manuscript peer review 08 June 2021 glucagon increase (12). Short-acting GLP-1 RAs, specifically target PPG with a predominant gastric emptying effect, while long-acting GLP-1 RAs, exert their effect predominantly through pancreatic functions, resulting in a lesser impact on PPG but larger overall reductions in FPG (12). Two once-daily titratable FRCs of basal insulin and GLP-1 RA are available which are approved for use in adults with type 2 diabetes.…”

Expert Opinion on the Therapeutic Use of the Fixed-Ratio Combination of Insulin Glargine 100 U/mL and Lixisenatide: a Central/Eastern European Perspective

“…There is a clear scientific rationale for combining a basal insulin, which mainly reduces the fasting plasma glucose (FPG) by decreasing hepatic glucose production and glucagon secretion but increases body weight, with a GLP-1 RA, which further improves the FPG but also reduces postprandial plasma glucose (PPG) peaks. GLP-1 RAs increase glucose-dependent insulin secretion, decrease glucagon secretion, and reduce the gastric emptying rate, food intake and body weight [2]. The fixed-ratio coformulation of these drugs has several advantages compared to basal-bolus insulin treatment or separate administration of the components, including a less complex and more convenient dosing schedule, fewer injections, easier titration, and lower insulin and GLP-1 RA doses.…”

“…The fixed-ratio coformulation of these drugs has several advantages compared to basal-bolus insulin treatment or separate administration of the components, including a less complex and more convenient dosing schedule, fewer injections, easier titration, and lower insulin and GLP-1 RA doses. In addition, the titration of FRCs has been shown to improve the gastrointestinal tolerability of the GLP-1 RA component compared to individual administration owing to slower uptitration than when the GLP-1 RA is administered alone [2].…”

“…The efficacy and safety of the two FRCs (iGlarLixi and iDegLira) were investigated and established in the LixiLan and DUAL clinical development programmes, respectively [2]. The DUAL programme, which consisted of nine randomized clinical trials, confirmed that oncedaily iDegLira generally achieved better glycaemic control than basal insulin or liraglutide alone, was associated with a lower risk of hypoglycaemic events, and had a more favourable patient weight profile than that of basal insulin alone [2].…”