Biosimilar and generic formulations of novel antidiabetic drugs: the role of liraglutide in clinical pharmacology of type 2 diabetes

KEYWORDS:

• Biosimilar
• diabetes
• generics
• GLP-1
• liraglutide
• treatment

There is increasing interest in biosimilar and generic formulations of novel antidiabetic drugs since the patent for liraglutide and other agents used for the treatment of patients with type-2 diabetes (T2DM), such as sitagliptin and dapagliflozin, are going to expire soon in many countries [1]. Some investigations are currently undergoing to assess the bioequivalence and safety of new generic formulations, and a phase I study is investigating the bioequivalence and safety of liraglutide, produced and marketed worldwide for more than 10 years by Novo Nordisk for T2DM patients, in comparison to a new biosimilar of the drug [2]. This may potentially create a clinical dilemma, as these drugs are still largely used in everyday clinical practice. For instance, a recent evaluation of antidiabetic medications used during the past few years in Romania has shown that sitagliptin and dapagliflozin were the most prescribed novel antidiabetic drugs, although biguanides, sulfonylureas, and insulin accounted for most of the prescriptions [3]. In another study performed earlier in England, sitagliptin, linagliptin, and liraglutide were among those in the frontline [4].

We have to emphasize that daily management of T2DM in clinical practice is now improved largely due to the availability of newer drugs, including both injectable, e.g. dulaglutide, and oral formulations, e.g. semaglutide; yet, the availability of some of these agents is still confined to few countries worldwide. By contrast, the vast majority of patients are treated with older generation medications, and it has been recently emphasized that 80% of individuals with diabetes live in countries with an overall availability of no more than 1% of the global diabetes-related expenditures [5]. There is therefore no surprise that novel anti-diabetic drugs, and particularly sodium-glucose co-transporter-2 inhibitors (SGLT-2i) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) are not affordable by most of the T2DM patients [5], despite their significant clinical benefit and overall beneficial safety profile [6–8].

In this context, the case of liraglutide is quite interesting. This agent has shown over the years a strong clinical efficacy on fasting and postprandial glucose parameters as well as on many additional cardiometabolic risk parameters, including body weight, blood pressure, plasma lipids, inflammation in patients with T2DM and in those with the metabolic syndrome [9,10]. Liraglutide was also the first GLP-1RA showing cardiovascular benefit in a cardiovascular outcome trial [11], most probably due to a direct action of liraglutide in the blood vessels, reducing atherosclerosis formation and progression [12]. In addition, liraglutide has been the first GLP-1RA approved for the treatment of obesity [13,14], and other studies have also demonstrated a benefit on NALFD and NASH with the use of this agent [15,16]. Regarding the benefit of liraglutide for NAFLD and NASH, a meta-analysis of the LEAD program has shown the safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes [17]; further, the LEAN-J is an interesting pilot study evaluating the effects of liraglutide in Japanese patients with NAFLD and NASH with glucose intolerance [18].

It is difficult to predict at the moment whether the forthcoming biosimilar and/or generic formulations of novel antidiabetic drugs, such as liraglutide, will be a real opportunity for our patients. A sine qua non of future biosimilar compounds is their equivalent effectiveness and safety at the time of approval and over time thereafter. This is particularly important when biosimilars or generics are produced by smaller companies with relative experience and in countries where regulatory oversight and/or quality controls are not as organized and/or not as strict. For instance, the injectable drug often depends its clinical value on the performance of the injection device; therefore, the device should also be evaluated when it is going to be on the market. In some areas of the world, such as the Asian continent, as reported by Taiwanese group, even low-dose GLP-1RA shows effectiveness [19]. This contributes to the discussion about the active use of liraglutide with lower cost and greater benefit in these areas.

Yet, the presence and availability of these generic formulations is expected to not only significantly contribute to a major reduction of the overall cost of the branded drugs but also, ultimately, an increase in the number of prescriptions and broader availability, which is expected to result in a much better management of T2DM in several nations [20]. We also wish to mention the existence of potential changes in patients’ quality of life and treatment satisfaction by liraglutide as well as the economic issues; indeed, there are studies showing that the combination of liraglutide and insulin can improve the quality of life [21]. Thus, the availability of these biosimilar and/or generic formulations could potentially contribute to overcome any clinical inertia still present in daily practice, given that the use of anti-diabetic medications with proven cardiovascular benefits is currently largely sub-optimal, despite the latest recommendations issued by international professional/scientific societies [22,23].

Indeed, in 2020 the American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), the European Society of Cardiology (ESC), and the American College of Cardiology (ACC) have all recommended in their distinct guidelines the use of either SGLT-2i or GLP-1RAs with proven cardiovascular benefit as first-line antidiabetic therapy in T2DM patients with overt atherosclerotic cardiovascular disease or for those at high risk of such disease [24–26]. Very interestingly, these suggestions were for the first time irrespective of the initial HbA1c values, and metformin was not recommended as a necessary first-line treatment [24–26]. This novel therapeutic approach has been confirmed in the latest ADA standards of medical care in diabetes in 2021 [27].

Currently, a proper and up-to-date management of T2DM and/or obesity is of greater importance due to the coronavirus pandemic, given that the presence of diabetes and obesity are associated with the most severe forms of COVID-19 and related mortality [28–30]; in addition, the profound changes in social and economic factors as well as the lack of access to appropriate health-care facilities for routine checks due to the pandemic have led to a significant deterioration of chronic disease management, including diabetes and obesity, and an increase of their cardiometabolic complications accompanied by large disparities among different geographical areas and ethnicities [31,32]. Insights and learnings from this pandemic can guide us toward an ultimately better management of cardiometabolic risk and toward overcoming current challenges [33–35].

It has also highlighted the importance of a coordinated action to ensure that subjects with T2DM, cardiovascular disease, heart failure, or chronic kidney disease are treated appropriately with cardioprotective compounds including SGLT-2i or GLP-1RAs [36]. COVID-19 pandemic has prevented appropriate hospital visits and, when regular medical attention is not available, it is better to use antidiabetic drugs that can be used safely. From this perspective, we wish to emphasize that liraglutide is safe to use, due to the low risk of hypoglycemia. In addition to this, recent studies suggest that liraglutide attenuated harmful response to hypoglycemia such as secretions of catecholamine without affecting recovery from hypoglycemia [37].

For all these reasons and provided that appropriate criteria and monitoring systems to guarantee both safety and equivalent efficacy are in place during approval and continuously thereafter, the introduction of novel biosimilar and/or generic formulations of novel antidiabetic drugs with proven cardiovascular and other benefits, e.g. cardiorenal or liver, may represent a unique and untapped opportunity for our patients, especially those who may not be able to currently afford the more expensive original formulations. We may be able to freely prescribe SGLT2i and GLP-1RAs with lesser financial penalties.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

This paper was not funded.