Some Differences Between Once-Weekly GLP-1 Agonists

Becky McCall

December 09, 2015

Newly available once-weekly glucagonlike peptide-1 (GLP-1) receptor agonists for the treatment of type 2 diabetes vary in terms of cardiometabolic outcomes and adverse effects, finds a systematic evidence review and meta-analysis.

Compared with other once-weekly GLP-1 agonists, the authors conclude that dulaglutide 1.5 mg (Trulicity, Eli Lilly), once-weekly exenatide 2 mg (Bydureon, AstraZeneca), and taspoglutide 20 mg showed greater reductions of HbA1c, fasting plasma glucose, and body weight.

In terms of adverse effects, taspoglutide 20 mg, which has now been withdrawn, had the highest risk for nausea, whereas the risk for hypoglycemia among once weekly GLP-1 agonists was similar.

The research is published online December 8 in the Annals of Internal Medicine and includes a total of 34 randomized controlled trials of albiglutide (Tanzeum, GlaxoSmithKline), dulaglutide, once-weekly exenatide, semaglutide (Novo Nordisk), and taspoglutide.

Dr Francesco Zaccardi, MD, from the Diabetes Research Centre, Leicester General Hospital, United Kingdom, led the study.

"We found several differences in the efficacy and safety profiles of once-weekly GLP-1 receptor agonists," he told Medscape Medical News. "Some of these drugs evidenced a better glucose control or body weight reduction, while others had an increased risk of side effects, such as nausea."

In comparison with placebo, he added that the findings confirm that the GLP-1 agonists, which are administered by subcutaneous injection, are effective in improving glucose control and reducing body weight, but this comes at the price of an increased risk of gastrointestinal side effects.

Commenting in an accompanying editorial, Dr Victor M Montori, MD, from the Mayo Clinic, Rochester, Minnesota, said that clinicians needed "high-quality evidence of the comparative effectiveness of various treatment options. Such evidence can inform patient-clinician conversations to determine which option best addresses the patient's situation.

"Ideally, the treatment will be easy to implement and affordable. Zaccardi and colleagues' network meta-analysis shows that meeting this basic standard in diabetes care remains, frustratingly and unfairly, a work in progress."

GLP-1 Agonists: First Comparison of Once-Weekly Drugs

The authors aim was to provide an analysis that might assist decision makers in providing patient-centered care.

"Beyond HbA1c, therapeutic decisions should be based on other outcomes, including body weight, risk for hypoglycemia, and gastrointestinal disorders," they write, noting that the findings should help doctors in following current guidelines.

To date, there have been no direct comparisons between the various once-weekly GLP-1 agonists. Against this background, Dr Zaccardi and colleagues used a network meta-analysis that estimates the comparative effectiveness of multiple treatments in the absence of direct evidence.

Data from a total of 21,126 participants were assessed across all the randomized clinical trials sourced from a range of electronic databases. Studies of GLP-1 agonists included were those with at least 24 weeks of follow-up reporting a cardiometabolic (primary outcome, HbA1c) or safety outcome.

Dr Zaccardi acknowledged that all studies had a degree of heterogeneity, as expected, and although taspoglutide has been withdrawn from the market for high rates of nausea, clinical data on the drug were included in the analysis.

HbA1c, Fasting Glucose Level, and Body Weight

The effects of the various GLP-1 agonists on several cardiometabolic outcomes, including blood pressure, lipids, and C-reactive protein, were similar, although the authors pinpointed a modest increase in heart rate with once-weekly exenatide vs albiglutide (mean difference, 3 bpm).

But HbA1c findings varied. "Compared with other once-weekly GLP-1 agonists, dulaglutide 1.5 mg, once-weekly exenatide, and taspoglutide 20 mg showed a greater reduction of HbA1c, fasting plasma glucose, and body weight," reported Dr Zaccardi.

Overall, once weekly GLP-1 agonists reduced HbA1c by a range of 0.9% to 1.4% percentage points compared with placebo. In particular, among the once-weekly GLP-1 agonists, the biggest difference in HbA1c was found in favor of dulaglutide 1.5 mg, vs taspoglutide 10 mg (0.4%).

The mean reduction in HbA1c values compared with placebo were:

  • -1.4% for dulaglutide 1.5 mg.

  • –1.3% for exenatide 2 mg.

  • –1.2% for dulaglutide 0.75 mg.

  • –1.1% for taspoglutide 20 mg.

  • –1.0% for albiglutide (defined as a single group because the majority of studies were designed to titrate the drug to 50 mg if necessary, and dose-specific data were available only for two studies).

  • –0.9% for taspoglutide 10 mg.

With respect to fasting plasma glucose, all once-weekly GLP-1 agonists showed significant reductions compared with placebo (reductions of 1.5 mmol/L to 2.2 mmol/L). When comparing one GLP-1 agonist with another, the greatest difference was 0.7 mmol/L in favor of once-weekly exenatide vs albiglutide.

Body weight was reduced with almost all GLP-1 agonists compared with placebo (maximum, 1.3 kg for taspoglutide 20 mg; minimum, 0.7 kg for dulaglutide 1.5 mg).

Only albiglutide and the lower doses of dulaglutide and taspoglutide did not show this reduction. The greatest difference in body weight was 1.5 kg, seen with taspoglutide 20 mg, compared with dulaglutide 0.75 mg.

While taspoglutide 20 mg had the highest risk of nausea, the risk of hypoglycemia among once-weekly GLP-1 agonists was comparable.

"Our results would therefore suggest clinically significant differences on three key indicators of metabolic control," write the authors.

"Of note, comparisons among licensed drugs showed no differences between once-weekly exenatide and the maintenance dose of dulaglutide (1.5 mg) for all three metabolic outcomes, and both treatments reduced HbA1c."

Lack of Head-to-Head Studies

Providing further comment in his editorial, Dr Montori highlighted that "reliable head-to-head comparisons of agents marketed by competitors within a class are rare." In lieu of such studies, clinicians have to use indirect comparisons as the best available evidence, he added.

"Selecting from within a drug class, particularly a new drug class, is difficult. Often, the available evidence does not provide a useful estimate of differences within the drug class.

"Apparent differences in efficacy and harm across agents in a drug class may disappear, for example, when researchers enroll consecutive patients (including those with other chronic conditions or with a different duration of diabetes), test the comparators using doses of similar potency, carefully identify and report adverse effects, and conduct this work independently of the manufacturers."

In conclusion, Dr Zaccardi remarked that prior to the study, they did not expect any particular result and that their aim was specifically to explore whether differences existed among GLP-1 agonists.

"Current [American Diabetes Association/European Association for the study of Diabetes] ADA/EASD guidelines for the treatment of hyperglycemia in type 2 diabetes advocate a personalized approach, taking into account a patient's characteristics and balancing potential risks and benefits of individual drugs. In this view, our findings could help clinicians to follow current ADA/EASD recommendations."

The primary funding source was from Sanofi (grant to the University of Leicester). Dr Zaccardi declares no relevant financial relationships; disclosures for the coauthors are listed in the article. Dr Montori has declared no relevant financial relationships.

Ann Intern Med. Published online December 8, 2015. Abstract, Editorial

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