Introduction
Type 2 diabetes (T2D) represents a global health challenge, with an alarming increase in prevalence worldwide. Development of T2D can be impacted by a range of factors, including diet, lifestyle and genetic predisposition. These factors vary in different races and ethnic groups,1 and regional variations can also impact the response to treatment and outcomes in T2D.2–4 For example, response to insulin therapy appears to be particularly poor in Asian Indians versus non-Asians,2 while African Americans and Hispanics show poorer glycemic control and experience a higher rate of diabetes-related complications versus non-Hispanic whites.3 Key factors known to impact on outcome and treatment vary between geographic areas, including obesity, cultural norms regarding diet, lifestyle and other health behaviors, prevailing treatment guidelines for glycemic control, blood pressure, lipids and cardiovascular management, as well as funding and nature of healthcare systems. Baseline differences, such as duration of diabetes, body weight and HbA1c, between US participants and Europeans have been reported in a study investigating risk factors for cardiovascular mortality and morbidity.5 The authors concluded that variation in regional cardiovascular risk factor management targets may result in these differences, and may therefore also contribute to observed differences in drug efficacy between regions.
Early optimal glycemic control and maintenance has been shown to prevent the development and progression of diabetes-related microvascular complications, and is a key treatment goal.6–8 As a progressive disease, T2D requires constant monitoring and timely treatment intensification, necessitating the introduction of glucagon-like peptide 1 receptor agonists (GLP-1 RA) and/or basal and/or bolus insulin following initial therapy with oral antidiabetic drugs (OADs).6–9 Real-world evidence suggests that if patients on basal insulin do not achieve glycemic control at 12 months after basal insulin initiation, they are unlikely to do so thereafter (IBM Watson). The ominous octet defines the multi-organ contribution to hyperglycemia, giving rise to the need for multiple pharmacologic options that target specific physiologic defects.10 Combination therapies known to have complementary mechanisms of action represent one approach to correcting specific glycemic disturbances. Recent studies have demonstrated that adding GLP-1 RA to basal insulin, either individually or as a fixed-ratio combination, results in equally effective or slightly superior glycemic control, with additional benefits of reduced to similar hypoglycemia, fewer GI adverse events compared with GLP-1 RA use alone, and weight loss.11–13
Insulin glargine/lixisenatide (iGlarLixi) is a once-daily titratable, fixed-ratio combination of insulin glargine 100 units/mL (iGlar) and the GLP-1 RA lixisenatide approved by the Food and Drug Administration and the European Medicines Agency. In the European Union, iGlarLixi is indicated in combination with metformin for the treatment of adults with T2D to improve glycemic control when this has not been provided by metformin alone or metformin combined with another OAD or with basal insulin. In the USA, iGlarLixi is indicated in patients unable to achieve glycemic control while on basal insulin <60U or lixisenatide. The rationale for the development of iGlarLixi was to combine the complementary actions of iGlar, which primarily improves fasting plasma glucose (FPG) levels,14 and lixisenatide, which affects postprandial glucose (PPG) levels by a glucose-dependent stimulation of insulin and suppression of glucagon. In addition, lixisenatide slows gastric emptying, thereby lessening PPG excursions.15–17 iGlarLixi has demonstrated efficacy and safety in phase II and III clinical trials.18–20 In two large multinational phase III clinical trials, once-daily iGlarLixi demonstrated greater reductions in HbA1c with no additional risk of hypoglycemia versus iGlar alone in insulin-naive patients inadequately controlled on OADs (LixiLan-O),16 and versus iGlar alone in insulin-experienced patients inadequately controlled on basal insulin±metformin (LixiLan-L).18
The USA and Canada are reported as having the highest and third highest global age-standardized diabetes prevalence, respectively, with disease-related healthcare expenditure higher than the rest of the world (RoW) combined.21 Given this high disease and economic burden, and the impact of ethnic and cultural differences on T2D risk, the analysis of treatment options within the North American population can provide useful insight for individualization of therapy within this region. In this post hoc analysis using patient-level data from the LixiLan-O and LixiLan-L randomized controlled trials (RCTs), we compared efficacy and safety outcomes, as well as treatment regimens, for patients treated with iGlarLixi, iGlar and lixisenatide in North America (NA; USA and Canada) compared with patients in the RoW.