Choices, Choices … Basal Insulin vs. GLP-1RA?

Should we use a GLP-1 receptor agonist (GLP-1RA) rather than basal insulin in patients with type 2 diabetes whose glycemic control are falling short on oral agents alone? Metformin is strongly recommended as initial therapy by both the American Diabetes Association (ADA) and American Association of Clinical Endocrinologists (AACE).^1,2  But most patients will require more than one agent to get to goal. The 2013 AACE guidelines suggest using a GLP-1RA as initial add-on therapy in patients with a hemoglobin A1C ≥ 7.5%, or > 9% without symptoms.² AACE cites the well-documented efficacy, weight loss, and low hypoglycemia risk of the GLP1-RAs to support this preference in patients who would benefit from weight loss.^2-4   There are several GLP-1RA products on the market now and several more are anticipated.  As treatment options explode, clinicians and patients continue to struggle with the BIG QUESTION – which injectable agent should I consider first?  Which therapeutic approach provides sustained benefits?  Which approach is safest?  The DURATION-3 Extension trial provides us with some much needed answers.

In 2010, the initial DURATION-3 trial report found that once-weekly exenatide was slightly more effective than once daily insulin glargine in terms of improving glycemic control over 26 weeks (A1c reduction = -1.5 vs. -1.3%, treatment difference −0·16%, 95% CI −0·29 to −0·03) in patients with type 2 diabetes who had failed to maintain glycemic control with metformin alone or metformin plus a sulfonylurea.⁴   The DURATION-3 Extension study continued to follow these patients for another 58 weeks (total of 84 weeks).⁴  Patients remained on their originally assigned randomized treatment, receiving either 2 mg of once-weekly exenatide or once-daily insulin glargine (dose titrated according to the Initiate Insulin by Aggressive Titration and Education [INITIATE] dosing algorithm).  Patients were required to continue the same dose of metformin through week 48.  Investigators could reduce or discontinue sulfonylurea therapy if hypoglycemia was a concern. Baseline characteristics in the DURATION-3 trial were comparable between treatment groups, with an average hemoglobin A1C of 8.3%, average body mass index of 32 kg/m², and duration of diabetes of 8 years. Seventy percent of participants who entered the study took metformin alone, and 30% took both metformin and a sulfonylurea.   

The primary efficacy outcome for the Extension Study was a change in hemoglobin A1C from baseline to study treatment end point defined as the last measurement prior to any change in therapy after week 48.  Secondary measures included change in weight, serum lipids, fasting glucose, time to failure to maintain glycemic control, and proportions of patients with hemoglobin A1C < 7 and ≤ 6.5. Safety measures included adverse events, clinical lab assessments, vital signs, and hypoglycemia.

A total of 456 patients were included in the intention-to-treat (ITT) analysis. Of these patients, 173 in the exenatide group and 173 in the insulin glargine group completed the entire 84 weeks of treatment. Results are summarized in Table 1.

Table 1 – Study Results

Results reported as least squares means ± SE
^†Symptomatic defined as patient with signs/symptoms of hypoglycemia with or without confirmatory blood glucose measurement.

Glycemic control significantly (but modestly) improved with once-weekly exenatide when compared to daily insulin glargine.  Not surprising, the reduction in fasting glucose was greater with insulin glargine.   We can assume that post-prandial blood glucose was substantially reduced by exenatide given that overall glycemic control was better in the exenatide group.  The proportion of patients who were able to achieve an A1c ≤ 6.5% was significantly greater with exenatide (number needed to treat = 10).  Weight loss with exenatide was maintained throughout the study.

Common adverse effects noted in the exenatide group included nausea and diarrhea during the first 26 weeks of treatment but relative few patients reporting these symptoms during the study extension period (nausea 2.1% and diarrhea 3.4%).  Serious adverse events reported in the exenatide group included one case of: pancreatitis, rectal polyp, cholelithiasis, B-cell lymphoma, and leukemia.  In the insulin glargine group, one case of esophageal carcinoma was observed.

While the study was well-designed, it was open-labeled and thus introduces the potential for bias. Reassuringly, metformin and sulfonylurea doses were reduced over the course of the study similarly in both treatment groups.  Unfortunately, predominately Caucasians (more than 80% in each group) were enrolled in the study — so the results may not be generalizable to other populations.

Insulin therapy causes hypoglycemia and weight gain.  Coupled with patient apprehension about self-administering daily injections, these factors can have a negatively impact on treatment adherence and quality of life. We know insulin is safe and effective, but if the patient does not take it, therapeutic goals won’t be met.  GLP-1RAs have several potential advantages over basal insulin.  Weight loss is a particularly attractive feature and the risk of hypoglycemia is substantially lower.  Whether once-weekly injections results in improved adherence in “real world” settings remains to be seen – but it’s clearly a potential advantage in some populations (e.g. elderly adults who depend on caregivers to administer medications).  While exenatide extended release has the potential advantage of once weekly administration, liraglutide, administered once daily, may improve glycemic control further still.^5,6

Some clinicians feel uneasy about using GLP-1RAs. As relatively new medications, we do not yet have evidence regarding their long-term safety or impact on hard endpoints such as cardiovascular events, kidney dialysis, or limb amputations. However, the DURATION-3 extension trial provides us with some additional data regarding the sustained effectiveness of exenatide and its tolerability.  Concerns about serious adverse effects associated with GLP-1RAs include pancreatitis, thyroid tumors, and cancer.  These fears were not confirmed in a recent meta-analysis⁷, but post-marketing reports of serious ADEs with the GLP-1RAs have been too frequent for comfort.

Acknowledging the potential risks, given the advantages of the GLP-1RAs over basal insulin, we believe a GLP-1RA should be the first add-on therapy after metformin in most patients with type 2 diabetes.  Are you ready to recommend a GLP-1RA before basal insulin?