Type 2 Diabetes Therapy Intensification: Part I: Insulin vs GLP-1 Agonists

Introduction

Type 2 diabetes is a complex, heterogeneous disease, and response to antihyperglycemic agents varies greatly among patients.¹ Therapy must be progressively escalated to help patients achieve or maintain glucose control.

Metformin monotherapy is typically first-line treatment for patients with a hemoglobin A1c (HbA1c) <9% at diagnosis. For individuals with an HbA1c ≥9% at diagnosis or who fail to achieve their target HbA1c after 3 months of metformin therapy, the American Diabetes Association (ADA) recommends adding another antihyperglycemic agent.¹

Many noninsulin agents are available; however, the ADA recommends basal insulin “when hyperglycemia is severe, especially if symptoms are present or any catabolic features (weight loss, ketosis) are present.”¹

Although basal insulin is highly effective, 43% to 50% of patients are unable to achieve glucose control.² Even when patients do achieve optimal glucose levels with basal insulin, the progression of disease compromises its effectiveness, and another antihyperglycemic agent must be added.²

When triple therapy fails or for patients with an HbA1c ≥10% at diagnosis, rapid-acting insulin (RAI) is commonly used to augment basal insulin.¹ However, the introduction of glucagon-like peptide-1 receptor agonists (GLP-1RAs) has provided clinicians with additional options for therapy intensification.¹

Agents in the GLP-1RA class mimic the role of endogenous GLP-1, stimulating pancreatic islet cells to release insulin in response to glucose ingestion.⁴ GLP-1RAs also inhibit glucagon release and slow the rate of glucose absorption in the intestine.⁵ Their ability to delay gastric emptying suppresses patients’ appetites, which can lead to weight loss.⁶

Several brands and formulations of GLP-1RAs are approved to treat type 2 diabetes, all of which have slightly different pharmacokinetic properties and clinical effects.⁴ GLP-1RAs are not recommended as first-line therapy, but may be introduced when a patient’s current regimen is no longer adequate. GLP-1RAs are available in long-acting and short-acting formulations. Recently, the US Food and Drug Administration (FDA) approved 2 fixed-ratio combinations, which combine a GLP-1RA with basal insulin in a single injection.¹

Clinical trial data show GLP-1RAs are as efficacious as postprandial RAI at improving glycemic control in patients with an inadequate response to basal insulin.³

The risks and benefits of RAIs and GLP-1RAs, along with treatment goals and patient preference, should be considered whenever therapy intensification is required.¹

Postprandial Insulin vs Prandial GLP-1RAs

When intensifying basal insulin with RAI, the 2 most common approaches are to administer a single injection of an RAI analog before the largest meal (basal-plus) or a single injection before every meal (basal-bolus).^1,4 Both regimens are effective at reducing the HbA1c to the ADA’s recommended target of ≤7%.^1,4 However, basal insulin increases the risk of hypoglycemia and contributes to weight gain.¹ Adding an RAI to therapy further increases the risk of hypoglycemia and weight gain, although less commonly with a basal-plus regimen than a basal-bolus regimen.⁷

Concerns about weight gain and hypoglycemia can leave clinicians and patients reluctant to increase RAI doses when needed, which compromises patients’ ability to reach the target HbA1c.⁸

A growing amount of clinical trial data support the use of GLP-1RAs as an alternative to RAIs for patients who cannot achieve HbA1c targets with basal insulin and require combination injectable therapy.³ GLP-1RAs do not contribute to weight gain and are associated with a lower risk of hypoglycemia than RAIs.^1,7,8

Studies have looked at the efficacy and safety of short-acting and long-acting GLP-1RAs. Numerous systematic analyses or meta-analyses of GLP-1RA intensification trials have been published, but differences in trial protocols have complicated cross-trial comparisons.⁴