Should GLP-1 Receptor Agonists Be the First Line of Treatment for Type 2 Diabetes?

Introduction

Type 2 diabetes (T2DM) is a chronic, progressive disease with a course that typically evolves over decades, yet the long-term safety and efficacy of most antihyperglycemic agents have not been well studied. In this issue of Diabetes Technology & Therapeutics, Henry et al. report data on the efficacy and safety of patients with T2DM treated with exenatide once weekly (QW) over 6 years of follow-up. ¹ In the original study, 297 subjects treated with lifestyle, monotherapy with metformin, sulfonylureas, or thiazolidinediones or a combination of two of these drugs were randomized to treatment with exenatide BID or exenatide QW. Subjects completing the initial study were then offered participation in an uncontrolled, open-label, open-ended extension. Of the 258 subjects entering the extension phase, 136 (46% of the original randomized group) completed 6 years of follow-up. This group experienced sustained reductions in A1c (−1.6%) and body weight (−4.2 kg) and, in addition, had improvements in beta-cell function and insulin resistance. Remarkably, over the period of observation, relatively few subjects required insulin therapy. Perhaps even more remarkably, 78 (57%) of the subjects were able to maintain glucose control for 6 years without any additional antihyperglycemic medication. Although the uncontrolled, open-label nature of the study limits the conclusions that can be drawn, these provocative data suggest that, at least in some individuals, treatment with the GLP-1 receptor agonist can alter the natural history of T2DM. This raises an interesting question. Should we rethink current treatment paradigms? Specifically, should GLP-1 receptor agonists be considered as first-line therapy for the treatment of T2DM?

Current T2DM Treatment Paradigms

Current treatment guidelines have evolved over the years as new agents to treat diabetes have become available. ^2,3 Almost all now recommend initial therapy with metformin followed by intensification with other agents in a stepwise manner as necessary to achieve glycemic targets. The rationale for using metformin as the first agent includes its efficacy, low risk of hypoglycemia, absence of weight gain, long record of safety, and cost-effectiveness. Notably, this stepwise approach focuses on controlling glucose, but does not address the underlying pathophysiology. This could explain why diabetes typically progresses and additional medications are needed to control glycemia over time. Another potential flaw in this approach to the management of hyperglycemia is that it does not address cardiovascular risk per se.

Multiple Metabolic Abnormalities Contribute to Hyperglycemia in T2DM

The pathophysiology of T2DM is complicated and involves multiple metabolic abnormalities that contribute to the onset and progression of hyperglycemia. ⁴ Insulin resistance and impaired insulin secretion are primary abnormalities that precede and predict the development of T2DM and worsen as the disease progresses. ⁵ In addition, alpha cell function is abnormal, leading to basal hypersecretion and impaired prandial suppression of glucagon, ⁴ driving an increase in hepatic glucose production. There are also defects in incretin hormone action (GLP-1 and GIP) that contribute to fasting and postprandial hyperglycemia. ⁶ T2DM is also characterized by upregulation of the SGLT-2 glucose transporter in the proximal tubule of the kidneys, facilitating greater glucose reabsorption and contributing to hyperglycemia. ⁷ Finally, overweight and obesity are strong risk factors for the development of T2DM and are present in 75%–85% of patients with the disease.

Rationale for Using GLP-1 Receptor Agonists Early in the Treatment of T2DM

The incretin hormone GLP-1 uniquely addresses many of the metabolic abnormalities present in established T2DM (Table 1). In addition to enhancing insulin secretion and suppressing glucagon secretion in a glucose-dependent manner, GLP-1 also increases peripheral glucose disposal and decreases hepatic glucose production to decrease glucose. Moreover, GLP-1 decreases the rapid gastric emptying typical of uncontrolled diabetes and has direct effects on central appetite centers to decrease food intake and promote weight loss. Thus, GLP-1 receptor agonists have the potential to address many of the multiple metabolic abnormalities present in T2DM.

In addition to addressing the underlying pathophysiology, there are pragmatic clinical reasons to prefer GLP-1 receptor agonists for the treatment of T2DM. First, GLP-1 receptor agonists are highly effective antihyperglycemic agents. Head-to-head studies have demonstrated that GLP-1 receptor agonists are at least comparable and usually superior to most oral medications and even insulin (both basal and prandial). As demonstrated in the Henry study, the long-term efficacy and durability of GLP-1 receptor agonists can be impressive, unlike many oral medications. ¹ Second, glycemic control can be achieved in the majority of patients without precipitating hypoglycemia, because of the glucose-dependent mechanism of action of these drugs acting through the GLP-1 receptor. ⁸ Third, treatment with GLP-1 receptor agonists is typically associated with modest weight loss of 2.5–3.5 kg. ⁹ Substantial evidence indicates that even modest decreases in body weight can improve metabolic function. Finally, the option to dose daily or once weekly (as in the present report) without regard to time of day or meals can simplify regimens and may improve adherence.

GLP-1 receptor agonists are effective and well tolerated in special populations such as the elderly, ¹⁰ those with chronic kidney disease, ¹¹ and those with cardiovascular disease. ¹² Since T2DM is associated with an increase in cardiovascular risk, it is relevant that GLP-1 receptor agonists are also associated with modest reductions in systolic blood pressure and improvements in low-density lipoprotein and high-density lipoprotein cholesterol and triglycerides. Recent cardiovascular outcome trials with lixisenatide, liraglutide, and semaglutide indicate that GLP-1 receptor agonists can be safely used in patients at high cardiovascular risk and may even decrease the risk of major adverse cardiovascular events, including cardiovascular death (liraglutide). ^{12 –14}

Arguments Against Using GLP-1 Receptor Agonists as First-Line Therapy

Despite the many features of GLP-1 receptor agonists that make them attractive as first-line therapy, there are several barriers to their broad uptake early in the treatment paradigm (Table 1). First, GLP-1 receptor agonists are associated with an increased risk of nausea, vomiting, diarrhea, and other gastrointestinal adverse events that may limit adherence. ⁹ As is the case with metformin, these adverse events are typically self-limiting with continued use and can be minimized with slow titration. Second, the need for injection can present a barrier for some patients and providers. This barrier can often be overcome with education. Third, although there have been a large number of patients in controlled trials and a substantial clinical exposure supporting the safety and tolerability of these agents, there remain outstanding concerns about pancreatitis and other rare adverse events. ¹⁵ Finally, and perhaps most importantly, as the GLP-1 receptor agonists are newer drugs, they are expensive and even when insurance companies cover the costs of the drugs, they typically require patients to have “failed” on at least metformin and sulfonylureas.

Summary

The treatment of T2DM continues to evolve as new agents are approved and as new clinical trials provide evidence of the efficacy, long-term safety, and cardiovascular benefits of these drugs. Guidelines will need to evolve as well to ensure that we achieve optimal outcomes in our patients. GLP-1 receptor agonists, among all antihyperglycemic agents, have a unique profile that addresses the complex pathophysiology and clinical needs of subjects with T2DM and should be considered for use early in the treatment paradigm.