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

When basal insulin no longer provides adequate glucose control in type 2 diabetes, a rapid-acting insulin or a glucagon-like peptide-1 receptor agonist may be used to intensify therapy.


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