Type 2 Diabetes Therapy Intensification: Part II: GLP-1 Agonist Adverse Effects and Fixed-Ratio Combinations

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.

Click here to read Part I of this article.

Adverse Effects of GLP-1RAs

The primarily adverse effects of GLP-1RAs are gastrointestinal and consist of nausea, vomiting, and diarrhea.9,13 Up to half of patients taking a GLP-1RA may experience nausea, which typically resolves within the first week and rarely leads to treatment discontinuation.9 Some patients develop upper respiratory infection or injection-site reactions.6,10 

In long-term studies of GLP-1RAs, discontinuation rates resulting from adverse events ranged from 4% to 21%.6 Some cases of pancreatitis have been reported with GLP-1RA use, but causality has not been established.9 In addition to class effects, each GLP-1RA has a unique safety profile, which must be weighed when choosing between them.

A meta-analysis of trials that added a GLP-1RA or an RAI to basal insulin found both approaches produced similar rates of symptomatic or severe hypoglycemia. However, patients taking a GLP-1RA with basal insulin were more likely to reach a target HbA1c <7.0% without experiencing symptomatic hypoglycemia than patients taking an RAI.14

Fixed-Ratio Combinations

Of the 2 FDA-approved fixed-ratio combinations, 1 pairs basal insulin with lixisenatide, and the other pairs it with liraglutide.1 A meta-analysis of trials that combined any GLP-1RA with basal insulin, including fixed-ratio combinations, found no significant difference in HbA1c outcomes among GLP-1RA/basal insulin regimens, basal-plus regimens, or basal-bolus regimens.8 However, the once-daily fixed-ratio combinations were better than insulin up-titration or basal insulin plus placebo at reducing HbA1c levels, with no increase in hypoglycemia and less weight gain.8


Many patients with type 2 diabetes require basal insulin with disease progression. When basal insulin no longer provides adequate glucose control, an RAI or a GLP-1RA may be used to intensify basal insulin therapy. Adherence is essential for optimizing glucose control (both HbA1c and postprandial glucose targets). Adherence is also critical for reducing the risk for diabetes complications, including adverse cardiovascular outcomes. The reduced incidence of weight gain and hypoglycemia with GLP-1RAs make them an appealing alternative to RAIs for patients unable to achieve HbA1c targets with basal insulin.

Treatment cost, patient preferences, and the patient’s clinical picture are all important considerations when intensifying therapy after basal insulin failure. Studies are needed to identify biomarkers or patient factors that predict who is most likely to respond to a GLP-1RA vs RAI.

Related Articles


  1. American Diabetes Association. Pharmacologic approaches to glycemic treatmentDiabetes Care. 2017;40(Suppl 1):S64-S74. doi:10.2337/dc17-S011
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